Classification rationale

PM2 VUS

BMPR1A c.117C>T synonymous · exon 4

PM2 supporting: gnomAD v4.1 total allele frequency is 2.91252e-05, below the generic PM2 threshold of 0.0001.

PM2 → VUS

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.

Gene diagram · NM_004329.3 · variants mapped to exon structure

BMPR1A NM_004329.3

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting: gnomAD v4.1 total AF is 2.91252e-05, below the generic PM2 threshold of 0.0001.

The case has no applicable gene-specific VCEP or CSPEC, so the supplied generic PM2 supporting threshold of <=0.0001 was applied.gnomAD v2.1 reports total AF 1.0609554257260472e-05 (3/282764 alleles; 0 homozygotes).gnomAD v4.1 reports total AF 2.9125214875920388e-05 (47/1613722 alleles; 1 homozygote), with group maximum FAF 1.994e-05.

gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

Assessed · not applied · 4 not met · 12 not assessed

Pathogenic

PS2 Not assessed: no proband parental-testing results, confirmed parentage, or phenotype data establish a de novo origin.

PS3 Not assessed: no validated variant-specific functional assay result was identified for BMPR1A c.117C>T (p.Ser39=).

PS4 Not assessed: no case-control cohort, enrichment statistic, odds ratio, or likelihood ratio is available for the exact variant.

PM6 Not assessed: no suspected de novo proband report or meiosis and parentage evidence is available without parental testing.

PP1 Not assessed: no affected-relative genotypes, informative meioses, or phenotype-concordant segregation data are reported.

PP4 Not assessed: no patient-level phenotype or highly specific BMPR1A-associated syndrome presentation is documented for the exact variant.

PP5 Not met: ClinVar shows zero expert-panel submissions for the exact variant, and available laboratory assertions are benign rather than expert-panel pathogenic.

Benign

BA1 Not met: the highest provided allele frequency is 0.00049456, far below the generic BA1 threshold of 0.05.

BS1 Not met: the highest provided allele frequency is 0.00049456, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD v4.1 shows one homozygote, but healthy-adult status and phenotype are not established.

BS3 Not assessed: no validated variant-specific assay demonstrated preserved BMPR1A function for c.117C>T (p.Ser39=).

BS4 Not assessed: no tested clinically unaffected relatives carrying the variant or phenotype-ascertained non-segregation data are reported.

BP2 Not assessed: no second pathogenic allele or documented cis/trans phase is available for NM_004329.3:c.117C>T.

BP5 Not assessed: no evidence shows an alternative pathogenic variant or different molecular diagnosis explains the patient's phenotype.

BP6 Not met: ClinVar has zero expert-panel submissions, so the exact variant's laboratory Benign or Likely benign assertions cannot trigger BP6.

BP7 Not assessed: synonymous c.117C>T has SpliceAI max delta 0.00, but the required nucleotide-conservation assessment is unavailable.

N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 2.91252e-05; MAF= 0.00291%, 47/1613722 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.000169434; MAF= 0.01694%, 1/5902 alleles, homozygotes = 0); grpmax FAF= 1.994e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.06096e-05; MAF= 0.00106%, 3/282764 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138543; MAF= 0.01385%, 1/7218 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0029% · 47 / 1,613,722
1 hom · FAF 0.002%

Middle Eastern 1 / 5,902	0.017%
Remaining individuals 6 / 62,448	0.0096%
South Asian 4 / 91,066	0.0044% 1 hom
European (non-Finnish) 33 / 1,180,004	0.0028%
African/African American 2 / 74,894	0.0027%
East Asian 1 / 44,878	0.0022%

+ 4 not observed (Admixed American, European (Finnish), Amish, Ashkenazi Jewish)

gnomAD v2.1

0.0011% · 3 / 282,764
0 hom

Remaining individuals 1 / 7,218	0.014%
East Asian 1 / 19,948	0.005%
European (non-Finnish) 1 / 129,090	0.00077%

+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 460476)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV63135122, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

20301642 ↗ Juvenile Polyposis Syndrome. CLINVAR

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. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

26389505 ↗ Genetics of Colorectal Cancer (PDQ®): Health Professional Version. CLINVAR

35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Check your email

Reset your password

Enter an access code

Your allowance