0%
FHc.143delLikely pathogenic
Print report
Variant interpretation report

FH c.143del, p.(Asn48IlefsTer5)

NM_000143.4:c.143del NP_000134.2:p.(Asn48IlefsTer5) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FH

No gene-level summary was recorded for this case.

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
PVS1Very strong
PVS1 · very strong

This variant is a frameshift change in FH, NM_000143.4:c.143del, predicted to cause p.(Asn48IlefsTer5) / p.(N48Ifs*5). FH loss of function is an established germline disease mechanism, and this early truncating variant occurs in exon 2 with a predicted premature stop far upstream of the 3' end, supporting application of PVS1 under the generic ClinGen SVI PVS1 framework.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 rarity threshold of 0.1%, supporting PM2 at supporting strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 14 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The FH c.143del (p.(Asn48IlefsTer5), p.(N48Ifs*5)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2 in non-VCEP interpretation.

The variant is predicted to cause an early truncating frameshift in FH, and FH loss of function is an established germline disease mechanism, supporting PVS1 under the generic ClinGen SVI PVS1 framework; SpliceAI predicts no significant splice impact with a max delta score of 0.00.

Met · 2

PVS1 Very strongThis variant is a frameshift change in FH, NM_000143.4:c.143del, predicted to cause p.(Asn48IlefsTer5) / p.(N48Ifs*5). FH loss of function is an established germline disease mechanism, and this early truncating variant occurs in exon 2 with a predicted premature stop far upstream of the 3' end, supporting application of PVS1 under the generic ClinGen SVI PVS1 framework. Details ▾Hide ▴
Rule
Generic PVS1 fallback per ClinGen SVI recommendations for a predicted null variant in a gene where loss of function is an established disease mechanism.
Evidence considered
  • FH loss of function supported as a germline disease mechanism
  • Frameshift consequence predicted as p.(Asn48IlefsTer5) / p.(N48Ifs*5)
  • Variant maps to exon 2 on the MANE transcript
Still missing
  • Transcript relevance and nonsense-mediated decay are inferred from the available transcript/protein context rather than confirmed by RNA data.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 rarity threshold of 0.1%, supporting PM2 at supporting strength. Details ▾Hide ▴
Rule
Population frequency below the PM2 rarity threshold for non-VCEP interpretation.
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 3 · evaluated, threshold not reached

PM1 This variant has not been shown to occur in a well-established mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Evidence considered
  • No hotspot row identified for FH residue N48
Still missing
  • Cancer Hotspots review was flagged as uncertain and may warrant manual confirmation if PM1 becomes important.
Sources
hotspots ↗
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not meet the benign stand-alone frequency threshold of 1.0%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore does not exceed the benign strong frequency threshold of 0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • Absent from gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 14 · no assessment recorded

PS2 No confirmed de novo occurrence with parental relationship confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo evidence identified
Still missing
  • Parental testing data were not available.
  • No publication or database entry describing a confirmed de novo case was identified.
PS3 Variant-specific well-established functional studies were not identified. Available FH publications and curated literature links support the gene-disease mechanism, but they do not provide sufficient directly reviewed functional evidence for this exact variant to apply PS3. Details ▾Hide ▴
Evidence considered
  • OncoKB linked FH literature for functional review
  • Retrieved publications were gene-level/contextual rather than clearly variant-specific in the available evidence
Still missing
  • Direct review of any variant-specific functional study would be needed before applying PS3.
Sources
oncokb ↗PMID:11865300 ↗PMID:12761039 ↗PMID:12772087 ↗PMID:15937070 ↗
PS4 No case-control enrichment data or count of unrelated affected individuals with this exact variant was identified, so PS4 cannot be assessed from the available evidence. Details ▾Hide ▴
Evidence considered
  • Variant absent from retrieved ClinVar results
Still missing
  • No exact affected proband count was available.
  • No case-control comparison was identified.
Sources
clinvar ↗
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No PM6-type evidence identified
Still missing
  • No proband-level parental testing or family structure data were available.
PP1 No segregation data were identified for this exact variant, so PP1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • No segregation evidence identified
Still missing
  • No pedigree
  • meiosis count
  • or affected-relative genotypes were available.
PP4 No individual-level phenotype, tumor profile, or family history was provided that would allow assessment of whether the presentation is highly specific for an FH-related disorder. Details ▾Hide ▴
Evidence considered
  • No phenotype-specific dataset available for criterion use
Still missing
  • Clinical phenotype and family history data would be needed.
PP5 No reputable source assertion with sufficient exact-variant classification detail was identified for criterion use. Details ▾Hide ▴
Evidence considered
  • Variant absent from retrieved ClinVar results
Still missing
  • An exact-variant expert or clinical laboratory assertion would be needed if PP5 were considered.
Sources
clinvar ↗
BS2 No evidence was identified showing this variant in healthy adult individuals in a context sufficient to apply BS2. Details ▾Hide ▴
Evidence considered
  • No unaffected carrier evidence identified
Still missing
  • Well-phenotyped unaffected carrier data would be needed.
BS3 Variant-specific well-established functional studies showing no damaging effect were not identified, so BS3 cannot be applied. Details ▾Hide ▴
Evidence considered
  • Retrieved literature did not establish a benign functional result for this exact variant
Still missing
  • Directly reviewed benign functional data for this exact variant would be needed.
Sources
oncokb ↗PMID:11865300 ↗PMID:12761039 ↗PMID:12772087 ↗PMID:15937070 ↗
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No BS4 evidence identified
Still missing
  • Family-based data showing lack of segregation would be needed.
BP2 No phase data with another variant were identified, so BP2 cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No co-occurrence data identified
Still missing
  • Phase information and co-occurring variant data would be needed.
BP3 No evidence was identified that this variant lies in a repetitive region or a region without known function that would support BP3. Details ▾Hide ▴
Evidence considered
  • No BP3-supporting regional evidence identified
Still missing
  • Region-specific annotation would be needed if BP3 were being considered.
BP5 No alternate molecular explanation for the phenotype was provided that would support BP5. Details ▾Hide ▴
Evidence considered
  • No alternate-cause evidence identified
Still missing
  • Detailed phenotype and alternate diagnosis data would be needed.
BP6 No reputable source benign assertion for this exact variant was identified. Details ▾Hide ▴
Evidence considered
  • Variant absent from retrieved ClinVar results
Still missing
  • A benign exact-variant assertion from a reputable source would be needed if BP6 were considered.
Sources
clinvar ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this is a frameshift variant rather than a different nucleotide change producing the same amino acid substitution as a known pathogenic variant. Details ▾Hide ▴
Evidence considered
  • Variant consequence is frameshift
  • not missense
Sources
pvs1_variant_assessment
PM3 N/APM3 is not applied because this review is using generic ACMG criteria for FH tumor predisposition, where pathogenicity is not being established through recessive trans observations. Details ▾Hide ▴
Evidence considered
  • FH germline disease context reviewed as loss-of-function tumor predisposition
Sources
pvs1_gene_context
PM4 N/APM4 is not applied because this protein-length-changing variant is already a predicted loss-of-function frameshift for which PVS1 is the more appropriate criterion. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence already captured by PVS1 logic
Sources
pvs1_variant_assessment
PM5 N/APM5 is not applicable because this is not a missense change, and the available PM5 review could not support classic same-residue missense comparator logic for this variant. Details ▾Hide ▴
Evidence considered
  • No eligible same-residue missense comparator candidates identified
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Evidence considered
  • Frameshift consequence
Sources
pvs1_variant_assessment
PP3 N/APP3 is not applied because this is a frameshift variant rather than a missense or splice-region variant requiring computational pathogenicity support. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not add independent pathogenic evidence beyond the predicted truncating consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Missense predictors were not applicable/skipped for this deletion
Sources
spliceai ↗pvs1_variant_assessment
BP1 N/ABP1 is not applicable because this is not a missense variant in a gene where truncating variants are not known to cause disease; here the variant is a truncating frameshift in a gene with loss-of-function disease mechanism. Details ▾Hide ▴
Evidence considered
  • FH loss of function supported
  • Variant is a frameshift
Sources
pvs1_gene_contextpvs1_variant_assessment
BP4 N/ABP4 is not applied because this is a frameshift variant rather than a missense or synonymous variant suitable for benign computational prediction criteria. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not provide standalone benign evidence against the predicted truncating effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Variant is a truncating frameshift
Sources
spliceai ↗pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this is not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is a coding frameshift deletion
Sources
pvs1_variant_assessment

Identifiers

Gene
FH
Transcript
NM_000143.4
Coding (HGVS c.)
NM_000143.4:c.143del
Protein (HGVS p.)
NP_000134.2:p.(Asn48IlefsTer5)
GRCh38
chr1:241517305 AT>A
GRCh37
chr1:241680605 AT>A

Gene diagram

Every interpreted variant in FH, mapped onto the exon structure of NM_000143.4. Select a row to find it on the plot.

FHNM_000143.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 is not applied because this is a frameshift variant rather than a missense or splice-region variant requiring computational pathogenicity support. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not add independent pathogenic evidence beyond the predicted truncating consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Missense predictors were not applicable/skipped for this deletion
Sources
spliceai ↗pvs1_variant_assessment
BP4 N/ABP4 is not applied because this is a frameshift variant rather than a missense or synonymous variant suitable for benign computational prediction criteria. SpliceAI predicts no significant splice impact with a max delta score of 0.00, but that does not provide standalone benign evidence against the predicted truncating effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score 0.00
  • Variant is a truncating frameshift
Sources
spliceai ↗pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this is not a synonymous or intronic variant. Details ▾Hide ▴
Evidence considered
  • Variant is a coding frameshift deletion
Sources
pvs1_variant_assessment

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

4 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

  • Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    No paper-specific finding is recorded.
    PMID 11865300 ↗
  • Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
    No paper-specific finding is recorded.
    PMID 12761039 ↗
  • Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
    No paper-specific finding is recorded.
    PMID 12772087 ↗
  • Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
    No paper-specific finding is recorded.
    PMID 15937070 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 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

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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.