About ROS1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ROS1 c.5825G>A, p.Arg1942Gln
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
NM_002944.2:c.5825G>A is present at extremely low frequency in gnomAD v4.1 (overall AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes; grpmax FAF=8.75e-06). It is absent from gnomAD v2.1. The allele frequency is well below the 0.1% PM2 threshold for generic ACMG application.
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect. REVEL score 0.706 is above the pathogenic threshold, and SpliceAI predicts a strong cryptic acceptor gain (delta=0.99) that may alter splicing. BayesDel score 0.137 is discordant (benign-leaning). Two independent computational lines (REVEL for missense impact; SpliceAI for splice-altering potential) support a deleterious effect, meeting the PP3 threshold at supporting strength.
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
13 / 1,613,226 alleles
gnomAD v4.1: 13 / 1,613,226 alleles. Recorded AF 8.05839e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.990 maximum delta
Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer.
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.
26 criteria with recorded statuses: 2 met · 16 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002944.2:c.5825G>A (p.Arg1942Gln) is a missense variant in exon 37 of the ROS1 gene, encoding a receptor tyrosine kinase implicated in familial lung cancer and hereditary breast cancer.
This variant is present at extremely low frequency in gnomAD v4.1 (AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes) and is absent from gnomAD v2.1. The grpmax filtering allele frequency is 8.75e-06, well below the 0.1% threshold for PM2 at supporting strength.
In silico predictors are predominantly deleterious: REVEL score 0.706 (pathogenic-leaning) and SpliceAI max delta 0.99 (predicts acceptor gain with potential splice-altering effect). PP3 is applied at supporting strength.
The variant is absent from ClinVar and COSMIC. No variant-specific functional studies, de novo reports, segregation data, or case-control analyses are available in the case materials.
PVS1 is not applicable as this is a missense variant. The variant does not lie at a canonical splice consensus position and falls outside the null-variant buckets defined by the ClinGen PVS1 framework (PMC6185798).
Only two supporting-level criteria (PM2_Supporting, PP3) are met. Per the ACMG/AMP 2015 combination rules, two supporting criteria are insufficient to reach a Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_002944.2:c.5825G>A is present at extremely low frequency in gnomAD v4.1 (overall AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes; grpmax FAF=8.75e-06). It is absent from gnomAD v2.1. The allele frequency is well below the 0.1% PM2 threshold for generic ACMG application. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=8.06e-06 (13/1
- 613
- 226 alleles
- 0 homozygotes)
- Grpmax FAF=8.75e-06
- Highest subpopulation AF: East Asian 4.46e-05 (2/44
- 862)
- All frequencies well below 0.1% PM2 threshold
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score 0.706 is above the pathogenic threshold, and SpliceAI predicts a strong cryptic acceptor gain (delta=0.99) that may alter splicing. BayesDel score 0.137 is discordant (benign-leaning). Two independent computational lines (REVEL for missense impact; SpliceAI for splice-altering potential) support a deleterious effect, meeting the PP3 threshold at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.706 (pathogenic-leaning
- above 0.644 threshold)
- SpliceAI: max delta 0.99 (acceptor gain AG=0.99
- AL=0.56)
- BayesDel: 0.137147 (discordant
- benign-leaning)
Still missing
- BayesDel is discordant
- RNA studies could resolve splice prediction
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo data are available for NM_002944.2:c.5825G>A. No publications or database records report a de novo observation of this variant. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature
Still missing
- De novo testing data would be required to assess PS2
PS3 No variant-specific functional data are available for p.Arg1942Gln. OncoKB reports Unknown Oncogenic Effect. No PMIDs with experimental characterization of this variant were identified in the case literature. Domain-level inference from gene function is not sufficient for PS3, which requires direct variant testing or systematic range characterization. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- No variant-specific functional studies identified in literature
Still missing
- Functional studies directly testing NM_002944.2:c.5825G>A (p.Arg1942Gln) are needed
Sources
PS4 No case-control or affected-prevalence data are available to demonstrate enrichment of this variant in affected individuals. Population allele counts from gnomAD (13/1,613,226) alone do not satisfy the PS4 requirement for statistically significant enrichment in cases versus controls. Details ▾Hide ▴
Evidence considered
- No case-control studies or affected-individual cohorts available
Still missing
- Case-control or cohort enrichment data would be required
PM1 p.Arg1942Gln does not lie in a statistically significant mutational hotspot per cancerhotspots.org. No VCEP- or literature-defined critical functional domain encompassing residue 1942 is available in the case materials. While ROS1 contains a tyrosine kinase domain, residue 1942 is positioned just N-terminal to the kinase domain (approx. residues 1945–2215), and no domain-specific functional characterization is provided to satisfy PM1. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant
- Residue 1942 lies upstream of the kinase domain
- no domain-level functional evidence for PM1
Still missing
- Domain-level functional characterization of the region encompassing residue 1942
PM6 No de novo data are available. No publications or database records report a de novo observation of NM_002944.2:c.5825G>A with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified
Still missing
- De novo testing with parental confirmation would be required
PP1 No segregation data are available for this variant. No family studies or cosegregation analyses were identified in the case materials. Details ▾Hide ▴
Evidence considered
- No segregation or family studies available
Still missing
- Family segregation data would be required
PP2 Insufficient data to apply PP2. ROS1 lacks a computed missense constraint metric (HCI Prior not available), and the gene does not have an established low rate of benign missense variation. While ROS1 missense variants have been reported in hereditary breast cancer (PMID:32906649), this alone does not satisfy the PP2 requirement for a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. Details ▾Hide ▴
Evidence considered
- HCI Prior: not available for ROS1
- No gnomAD missense constraint metric available in case materials
- ROS1 missense variants reported in hereditary cancer but PP2 threshold not met
Still missing
- Missense constraint metrics (Z-score
- oe ratio) for ROS1 would be needed
PP4 No patient-specific phenotype or clinical data are available in the case. PP4 requires that the variant is observed in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology, and no such clinical information is provided. Details ▾Hide ▴
Evidence considered
- No clinical phenotype or family history data available
Still missing
- Patient phenotype and family history information would be required
BA1 The overall gnomAD v4.1 allele frequency is 0.000081% (8.06e-06), far below the 1% BA1 threshold. The highest subpopulation frequency (East Asian) is 0.00446% (4.46e-05), also well below 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF: 8.06e-06 (0.000081%)
- Highest subpopulation AF (East Asian): 4.46e-05 (0.00446%)
- Both far below BA1 threshold of 1%
Sources
BS1 The overall gnomAD v4.1 allele frequency is 0.000081%, below the 0.3% BS1 threshold. The highest subpopulation frequency (East Asian) is 0.00446%, also well below 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 overall AF: 8.06e-06 (0.000081%)
- Highest subpopulation AF (East Asian): 4.46e-05 (0.00446%)
- Both far below BS1 threshold of 0.3%
Sources
BS2 No data on healthy adult carriers are available. BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder, and no such data are present in the case materials. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available
Still missing
- Observation in healthy adults with full penetrance data would be required
BS3 No functional studies demonstrating no deleterious effect of p.Arg1942Gln are available. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing. Details ▾Hide ▴
Evidence considered
- No functional studies demonstrating benign effect identified
Still missing
- Functional studies demonstrating normal protein function would be required
BS4 No segregation data demonstrating lack of cosegregation with disease are available. BS4 requires observation of the variant in affected family members without disease or inconsistent segregation patterns. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Family segregation data demonstrating non-segregation would be required
BP1 BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. ROS1 does not meet this requirement: missense variants in ROS1 have been reported in hereditary breast cancer (PMID:32906649), and the gene-level PVS1 context supports both LoF and potential missense disease mechanisms in familial lung cancer (PMID:41390056). The disease mechanism for ROS1 is not exclusively truncating. Details ▾Hide ▴
Evidence considered
- ROS1 missense variants reported in hereditary breast cancer (PMID:32906649)
- Gene-level disease mechanism is not exclusively LoF/truncating
- BP1 not applicable when missense is a recognized disease mechanism
BP2 No data on observation of this variant in trans with a known pathogenic variant are available. BP2 requires the variant to be observed in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in a dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans/cis configuration data available
Still missing
- Phase information with pathogenic variants would be required
BP4 Computational evidence is not uniformly benign. REVEL 0.706 predicts a damaging effect, and SpliceAI delta 0.99 predicts a splice-altering effect. Only BayesDel (0.137) suggests a benign impact. BP4 requires multiple lines of computational evidence to suggest no impact; the majority of available predictors indicate a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.706 (pathogenic-leaning)
- SpliceAI: 0.99 (splice-altering)
- BayesDel: 0.137 (only benign-leaning predictor
- insufficient for BP4)
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002944.2:c.5825G>A is a missense variant (p.Arg1942Gln) and does not fall into the null-variant buckets required for PVS1 (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Although SpliceAI predicts an acceptor gain (delta=0.99), the variant resides at coding position c.5825 in exon 37, 48 bases downstream of the acceptor splice junction, and does not disrupt the canonical splice consensus. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution (p.Arg1942Gln)
- Position c.5825 is in exon 37
- not at a canonical ±1
- 2 splice junction
- PVS1 variant bucket: 'other' — apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo ClinVar entry exists for a different nucleotide change resulting in the same amino acid substitution (p.Arg1942Gln). The variant is absent from ClinVar entirely. Details ▾Hide ▴
PM5 N/ANo same-residue ClinVar comparator variants (different amino acid change at Arg1942) were identified. The PM5 candidate harvest produced zero candidates, and no expert-panel pathogenic variants at this position are available. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 candidates at residue Arg1942
- Eligible for classic PM5 search: false
Sources
pm5_candidates
PP5 N/ANM_002944.2:c.5825G>A is absent from ClinVar. PP5 requires a reputable source (ClinVar 3-star expert panel) to have classified the variant as pathogenic. No ClinVar entry exists for this variant. Details ▾Hide ▴
BP5 N/ABP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available, and this criterion is not applicable without a confirmed alternate genetic cause in the proband. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis for disease identified
BP6 N/ANM_002944.2:c.5825G>A is absent from ClinVar. BP6 requires a reputable source (ClinVar 3-star expert panel) to have classified the variant as benign. No ClinVar entry exists for this variant. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice site. NM_002944.2:c.5825G>A is a missense variant (p.Arg1942Gln), not a synonymous variant, and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg1942Gln)
- not synonymous
PS5 N/ANo ClinVar pathogenic variant exists at the same amino acid residue (Arg1942) with a different nucleotide change. The variant is absent from ClinVar, and no comparator variants are available for a PS5 assessment. Details ▾Hide ▴
Identifiers
- Gene
- ROS1
- Transcript
- NM_002944.2
- Coding (HGVS c.)
- NM_002944.2:c.5825G>A
- Protein (HGVS p.)
- NP_002935.2:p.(Arg1942Gln)
- GRCh38
- chr6:117319983 C>T
- GRCh37
- chr6:117641146 C>T
Gene diagram
Every interpreted variant in ROS1, mapped onto the exon structure of NM_002944.2. Select a row to find it on the plot.
ROS1NM_002944.2
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 ROS1
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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
13 / 1,613,226 alleles
AF 8.06e-06 · 0 homozygotes · FAF 8.75e-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 8.1e-06 · 13 / 1,613,226 alleles · 0 hom · FAF 8.7e-06
| East Asian2 / 44,862 | 4.5e-05 |
| South Asian3 / 91,056 | 3.3e-05 |
| Remaining individuals1 / 62,436 | 1.6e-05 |
| European (non-Finnish)7 / 1,179,590 | 5.9e-06 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.05839e-06; MAF= 0.00081%, 13/1613226 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.45812e-05; MAF= 0.00446%, 2/44862 alleles, homozygotes = 0); grpmax FAF= 8.75e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.706
- BayesDel
- 0.137
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect. REVEL score 0.706 is above the pathogenic threshold, and SpliceAI predicts a strong cryptic acceptor gain (delta=0.99) that may alter splicing. BayesDel score 0.137 is discordant (benign-leaning). Two independent computational lines (REVEL for missense impact; SpliceAI for splice-altering potential) support a deleterious effect, meeting the PP3 threshold at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.706 (pathogenic-leaning
- above 0.644 threshold)
- SpliceAI: max delta 0.99 (acceptor gain AG=0.99
- AL=0.56)
- BayesDel: 0.137147 (discordant
- benign-leaning)
Still missing
- BayesDel is discordant
- RNA studies could resolve splice prediction
Sources
BP4 Computational evidence is not uniformly benign. REVEL 0.706 predicts a damaging effect, and SpliceAI delta 0.99 predicts a splice-altering effect. Only BayesDel (0.137) suggests a benign impact. BP4 requires multiple lines of computational evidence to suggest no impact; the majority of available predictors indicate a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.706 (pathogenic-leaning)
- SpliceAI: 0.99 (splice-altering)
- BayesDel: 0.137 (only benign-leaning predictor
- insufficient for BP4)
Sources
BP7 N/ABP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice site. NM_002944.2:c.5825G>A is a missense variant (p.Arg1942Gln), not a synonymous variant, and is therefore not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Arg1942Gln)
- not synonymous
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). REVEL score = 0.706. BayesDel score = 0.137147.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
13 / 1,613,226 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.990
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_002944.2%3Ac.5825G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-117641146-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-117319983-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-117319983-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002944.2%3Ac.5825…
- OncoKB ↗www.oncokb.org/gene/ROS1/R1942Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ROS1+c.5825G%3EA
- 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= 8.05839e-06; MAF= 0.00081%, 13/1613226 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.45812e-05; MAF= 0.00446%, 2/44862 alleles, homozygotes = 0); grpmax FAF= 8.75e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). REVEL score = 0.706. BayesDel score = 0.137147.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer.
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.