Classification rationale

BS1BP4 Likely Benign

MET c.110T>C

The MET c.110T>C (p.Val37Ala) variant has been reported in ClinVar with likely benign and benign submissions.¹ This variant is present in population databases at a frequency above the BS1 threshold, with the highest observed frequency of 0.70588% in South Asian individuals in gnomAD v2.1 and 0.68732% in South Asian individuals in gnomAD v4.1, arguing against a rare pathogenic germline variant.² No well-established variant-specific functional study was identified to support either a damaging or a normal effect.³ Computational evidence supports a benign interpretation, with SpliceAI predicting no significant splice impact (maximum delta score 0.00), REVEL of 0.142, and BayesDel of -0.247812.⁴

BS1 + BP4 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗

4 spliceai ↗revelbayesdel

Gene diagram · NM_001127500.3 · variants mapped to exon structure

MET NM_001127500.3

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000544625; MAF= 0.05446%, 879/1613956 alleles, homozygotes = 10) and has highest observed frequency in the South Asian population (AF= 0.00687323; MAF= 0.68732%, 626/91078 alleles, homozygotes = 10); grpmax FAF= 0.00642681.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000908223; MAF= 0.09082%, 255/280768 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00705882; MAF= 0.70588%, 216/30600 alleles, homozygotes = 1); grpmax FAF= 0.0062877.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.054% · 879 / 1,613,956
10 hom · FAF 0.64%

South Asian 626 / 91,078	0.69% 10 hom
Middle Eastern 9 / 6,060	0.15%
Ashkenazi Jewish 36 / 29,600	0.12%
Remaining individuals 46 / 62,496	0.074%
European (non-Finnish) 157 / 1,179,916	0.013%
Admixed American 3 / 59,978	0.005%
African/African American 2 / 75,022	0.0027%

+ 3 not observed (European (Finnish), Amish, East Asian)

gnomAD v2.1

0.091% · 255 / 280,768
1 hom · FAF 0.63%

South Asian 216 / 30,600	0.71% 1 hom
Ashkenazi Jewish 11 / 10,358	0.11%
Remaining individuals 4 / 7,146	0.056%
European (non-Finnish) 23 / 128,602	0.018%
African/African American 1 / 24,190	0.0041%

+ 3 not observed (Admixed American, East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (3 clinical laboratories). (ClinVarID = 41610)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.142. BayesDel score = -0.247812.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MET, a receptor tyrosine kinase, is recurrently altered by mutation or amplification in various cancer types.

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; COSV104627100, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots