About ALK
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ALK c.4148T>C, p.(Ile1383Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes; grpmax FAF=4.29e-6). The allele frequency is well below the 0.1% threshold for PM2 under generic ACMG.
PP3Supporting
PP3 · supporting
REVEL predicts a damaging effect (score=0.861, above the 0.75 threshold). BayesDel is borderline (score=0.373, below 0.5) and SpliceAI predicts no splice impact (max delta=0.0). While in silico predictors are mixed, the strong REVEL score supports a deleterious prediction and is consistent with one ClinVar submitter (Ambry Genetics) citing in silico evidence for this variant. Applied at supporting strength due to lack of full multi-tool concordance.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
11 / 1,613,822 alleles
gnomAD v4.1: 11 / 1,613,822 alleles. Recorded AF 6.81612e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004304.4:c.4148T>C (p.Ile1383Thr) is a missense variant in exon 28 of the ALK gene. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes).
In silico analysis with REVEL predicts a damaging effect (score=0.861), though additional predictors are equivocal (BayesDel score=0.373; SpliceAI max delta=0.0). Ambry Genetics cited in silico evidence (PP3) in their ClinVar submission.
ClinVar Variation ID 575890: classified as Uncertain Significance by 2 clinical laboratories (review status: criteria provided, single submitter). No expert panel classification exists.
No variant-specific functional data, cosegregation data, case-control data, or de novo reports were identified in the literature. OncoKB classifies this variant as Unknown Oncogenic Effect.
This variant is not a null variant (PVS1 not applicable) and does not fall in a statistically significant mutational hotspot (PM1 not met). No same-residue pathogenic comparators were identified (PM5 not applicable).
No benign criteria are met: the variant is too rare for BA1/BS1, not observed in homozygous state (BS2 not met), and no benign functional evidence exists (BS3 not met). In silico predictors are mixed and do not support multiple lines of benign evidence (BP4 not met). BP1 is not applicable as ALK missense variants are established disease-causing mechanisms.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF=6.82e-6, 11/1,613,822 alleles, 0 homozygotes; grpmax FAF=4.29e-6). The allele frequency is well below the 0.1% threshold for PM2 under generic ACMG. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent. gnomAD v4.1: AF=6.82e-6 (11/1
- 613
- 822 alleles)
- highest in NFE (AF=8.48e-6
- 10/1
- 179
- 752). gnomAD-Canada: absent. All frequencies well below 0.1% PM2 threshold.
Sources
PP3 SupportingREVEL predicts a damaging effect (score=0.861, above the 0.75 threshold). BayesDel is borderline (score=0.373, below 0.5) and SpliceAI predicts no splice impact (max delta=0.0). While in silico predictors are mixed, the strong REVEL score supports a deleterious prediction and is consistent with one ClinVar submitter (Ambry Genetics) citing in silico evidence for this variant. Applied at supporting strength due to lack of full multi-tool concordance. Details ▾Hide ▴
Evidence considered
- REVEL: 0.861 (damaging). BayesDel: 0.373 (borderline). SpliceAI max delta: 0.0 (no splice impact). Ambry Genetics ClinVar submission (SCV003898311) cited PP3 based on in silico analysis.
Still missing
- BayesDel and SpliceAI do not corroborate REVEL's damaging prediction
- ideally multiple in silico lines should agree.
Sources
Not met · 16 · evaluated, threshold not reached
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional data. No publications with experimental functional characterization of p.Ile1383Thr were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. No publications with functional data for c.4148T>C identified.
Still missing
- No experimental functional characterization of this variant exists in the curated literature.
Sources
PS4 No variant-specific case-control or prevalence data in affected individuals are available. The variant has been observed in ClinVar as VUS by 2 clinical laboratories, but no enriched prevalence in cases versus controls has been demonstrated. Details ▾Hide ▴
Evidence considered
- ClinVar: 2 clinical laboratories classify as VUS. No case-control studies or cohort enrichment data for this variant.
Still missing
- No case-control or cohort prevalence data for this variant in neuroblastoma or other ALK-associated conditions.
Sources
PM1 This variant (p.Ile1383Thr) lies within the ALK kinase domain (residues ~1116-1392), a functionally important region. However, the residue is not a statistically significant hotspot per cancerhotspots.org, and no variant-specific domain-level evidence from the literature links this position to germline pathogenicity. Domain membership alone, without a specific mutational hotspot or functional domain characterization showing enrichment of pathogenic variants at or near this residue, is insufficient for PM1 under generic ACMG. Details ▾Hide ▴
Evidence considered
- Located in kinase domain (C-terminal lobe
- position 1383). Cancerhotspots.org: residue not significant. No literature evidence of pathogenic enrichment at this residue within the domain.
Still missing
- No domain-specific functional characterization or hotspot data linking this residue to germline pathogenicity.
Sources
PP1 No cosegregation data with disease in families are available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data identified.
Still missing
- No cosegregation data available.
PP2 No gene-level missense constraint data (e.g., gnomAD missense Z-score) were available in the evidence packet to assess whether ALK has a low rate of benign missense variation. Without explicit constraint metrics, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- No missense constraint metrics (mis_Z
- o/e) available for ALK in the case materials.
Still missing
- Gene-level missense constraint data not provided in case evidence.
PP4 No patient-specific phenotype or family history data are available for this case. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype or clinical data provided for this case.
Still missing
- Patient phenotype and family history not available for assessment.
PP5 ClinVar classifies this variant as Uncertain Significance (2 clinical laboratories, review status: criteria provided, single submitter). The classification is not pathogenic/likely pathogenic and the review status is not expert panel (3-star). PP5 requires a reputable source to have classified the variant as pathogenic. The cited ClinVar publications (PMID:20301782, GeneReviews; PMID:25394175, ACMG guideline) are gene-level references that do not mention this variant. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 575890: VUS
- 1-star review status. No expert panel classification. Associated PMIDs are gene-level references without variant-specific mention.
Sources
BA1 The variant allele frequency in gnomAD v4.1 is 6.82e-6 (0.00068%), far below the 1% BA1 threshold. BA1 is not met. Details ▾Hide ▴
BS1 The variant allele frequency in gnomAD v4.1 is 6.82e-6 (0.00068%), far below the 0.3% BS1 threshold. BS1 is not met. Details ▾Hide ▴
BS2 No homozygous individuals are observed in gnomAD v4.1 (0 homozygotes out of 1,613,822 alleles). BS2 requires observation in a healthy adult homozygous state for a fully penetrant disorder. Details ▾Hide ▴
BS3 No well-established functional studies show no damaging effect for this variant. No experimental functional data of any kind were identified for p.Ile1383Thr. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies identified.
Still missing
- No functional data available.
Sources
BS4 No non-segregation data with disease in families are available for this variant. Details ▾Hide ▴
Evidence considered
- No family studies or non-segregation data identified.
Still missing
- No segregation data available.
BP2 No evidence that this variant has been observed in trans with a pathogenic variant in a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
BP4 REVEL predicts a damaging effect (score=0.861). While SpliceAI is neutral (max delta=0.0) and BayesDel is borderline (0.373), the strong REVEL pathogenic prediction precludes BP4, which requires multiple lines of computational evidence suggesting no impact on gene product. The in silico evidence is mixed and does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.861 (damaging). BayesDel: 0.373 (borderline). SpliceAI max delta: 0.0. Mixed signals
- does not meet threshold for multiple lines suggesting no impact.
Sources
BP5 No evidence that this variant has been found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
BP6 ClinVar classifies this variant as Uncertain Significance, not benign/likely benign. The review status is 'criteria provided, single submitter' (1-star), not expert panel. No reputable source reports this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 575890: VUS
- 1-star review status. No benign classification from any source.
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution (p.Ile1383Thr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) applies only to predicted null variants; the variant does not fall into any PVS1 bucket. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 1383
- variant_bucket='other'
- apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo alternate nucleotide change at codon 1383 producing the same amino acid change (Ile1383Thr) has been reported as pathogenic. PS1 requires a different nucleotide substitution resulting in the same missense change that is established as pathogenic. Details ▾Hide ▴
Evidence considered
- No known pathogenic variant at this codon with same amino acid change from different nucleotide substitution.
PS2 N/ANo de novo occurrence data with confirmed paternity and maternity are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar submissions or literature.
PM3 N/ANo evidence that this variant has been found in trans with a pathogenic variant for a recessive disorder. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a missense substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss). Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at the same codon (Ile1383) was identified as a PM5 comparator. Automated candidate harvesting found no same-residue candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found 0 same-residue candidates. No expert panel pathogenic or likely pathogenic variant at codon 1383 identified.
Sources
pm5_candidates
PM6 N/ANo de novo occurrence data (without confirmed paternity/maternity) are available for this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature.
BP1 N/AALK missense variants are established causes of neuroblastoma predisposition (e.g., F1174L, R1275Q). The disease mechanism is not limited to truncating variants; both missense and truncating germline variants are associated with disease. BP1 applies only when a gene's disease mechanism is primarily through truncating variants. Details ▾Hide ▴
Evidence considered
- ALK LoF is a supported germline disease mechanism
- but well-established pathogenic missense variants also exist. Disease mechanism is not restricted to truncating variants.
Sources
pvs1_gene_context
BP3 N/AThis is a missense substitution, not an in-frame indel in a non-repeat region. BP3 applies to in-frame deletions/insertions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (p.Ile1383Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
PS5 N/ANo evidence that this variant has been found in trans with a pathogenic variant in the same gene. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
Identifiers
- Gene
- ALK
- Transcript
- NM_004304.4
- Coding (HGVS c.)
- NM_004304.4:c.4148T>C
- Protein (HGVS p.)
- NP_004295.2:p.(Ile1383Thr)
- GRCh38
- chr2:29196786 A>G
- GRCh37
- chr2:29419652 A>G
- ClinVar
- 575890
Gene diagram
Every interpreted variant in ALK, mapped onto the exon structure of NM_004304.4. Select a row to find it on the plot.
ALKNM_004304.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ALK
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
11 / 1,613,822 alleles
AF 6.82e-06 · 0 homozygotes · FAF 4.29e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,613,822 alleles · 0 hom · FAF 4.3e-06
| Remaining individuals1 / 62,482 | 1.6e-05 |
| European (non-Finnish)10 / 1,179,752 | 8.5e-06 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.81612e-06; MAF= 0.00068%, 11/1613822 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60046e-05; MAF= 0.00160%, 1/62482 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.861
- BayesDel
- 0.373
How the predictions were used
PP3 SupportingREVEL predicts a damaging effect (score=0.861, above the 0.75 threshold). BayesDel is borderline (score=0.373, below 0.5) and SpliceAI predicts no splice impact (max delta=0.0). While in silico predictors are mixed, the strong REVEL score supports a deleterious prediction and is consistent with one ClinVar submitter (Ambry Genetics) citing in silico evidence for this variant. Applied at supporting strength due to lack of full multi-tool concordance. Details ▾Hide ▴
Evidence considered
- REVEL: 0.861 (damaging). BayesDel: 0.373 (borderline). SpliceAI max delta: 0.0 (no splice impact). Ambry Genetics ClinVar submission (SCV003898311) cited PP3 based on in silico analysis.
Still missing
- BayesDel and SpliceAI do not corroborate REVEL's damaging prediction
- ideally multiple in silico lines should agree.
Sources
BP4 REVEL predicts a damaging effect (score=0.861). While SpliceAI is neutral (max delta=0.0) and BayesDel is borderline (0.373), the strong REVEL pathogenic prediction precludes BP4, which requires multiple lines of computational evidence suggesting no impact on gene product. The in silico evidence is mixed and does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.861 (damaging). BayesDel: 0.373 (borderline). SpliceAI max delta: 0.0. Mixed signals
- does not meet threshold for multiple lines suggesting no impact.
Sources
BP7 N/AThis is a missense variant (p.Ile1383Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.861. BayesDel score = 0.373142.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301782 ↗ALK-Related Neuroblastic Tumor Susceptibility.Adam MP et al. · 1993GeneReviews chapter on ALK-related neuroblastic tumor susceptibility. Provides general clinical and genetic overview of germline ALK variants in neuroblastoma predisposition. NM_004304.4:c.4148T>C was not specifically discussed.Does not name this variant
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. A general clinical guidance document that does not discuss individual variants or genes at the variant level.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,613,822 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
2 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/575890/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/2-29419652-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr2-29196786-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/2-29196786-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004304.4%3Ac.4148…
- OncoKB ↗www.oncokb.org/gene/ALK/I1383T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ALK+c.4148T%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.81612e-06; MAF= 0.00068%, 11/1613822 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60046e-05; MAF= 0.00160%, 1/62482 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 575890)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.861. BayesDel score = 0.373142.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ALK, a receptor tyrosine kinase, is recurrently altered by chromosomal rearrangements in various cancer types including anaplastic large cell lymphoma
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.