NM_001127500.3:c.3852+5T>C is an intronic substitution at the +5 position of the splice donor in intron 19 of MET. PVS1 is not applicable as the variant falls outside the canonical ±1,2 splice consensus and no functional data demonstrate a null effect.1 SpliceAI predicts no significant splice impact (max delta score 0.09), meeting BP4 at the supporting level.2 The variant is present in gnomAD v2.1 at an allele frequency of 0.0089% (25/280,544 alleles) and in gnomAD v4.1 at 0.022% (353/1,614,074 alleles) including 1 homozygote, which is inconsistent with a rare pathogenic variant for a dominant cancer predisposition disorder but does not meet BS1 (>0.3%) or BA1 (>1%) thresholds.3 ClinVar reports a consensus classification of Likely benign from 5 clinical testing laboratories (GeneDx, Ambry Genetics, Labcorp/Invitae, Myriad Genetics, PreventionGenetics), meeting BP6 at the supporting level. Two laboratories report Uncertain significance.4 No functional studies, segregation data, de novo observations, case-control studies, or variant-specific literature were identified for this variant; all remaining pathogenic and benign criteria are either not met or not applicable.5
MET
Final classification
Likely Benign
MET c.3852+5T>C · p.?
MET
NM_001127500.3:c.3852+5T>C is an intronic substitution at the +5 position of the splice donor in intron 19 of MET. PVS1 is not applicable as the variant falls outside the canonical ±1,2 splice consensus and no functional data demonstrate a null effect.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP4 supporting, BP6 supporting; combination = 2 supporting benign, which maps to Likely Benign.
Classification rationale
BP4BP6
Likely Benign
MET c.3852+5T>C
BP4 + BP6
→
Likely Benign
1
pvs1_variant_assessmentspliceai ↗
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= 0.000218701; MAF= 0.02187%, 353/1614074 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000282211; MAF= 0.02822%, 333/1179970 alleles, homozygotes = 0); grpmax FAF= 0.00025697.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.91126e-05; MAF= 0.00891%, 25/280544 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000420168; MAF= 0.04202%, 3/7140 alleles, homozygotes = 0); grpmax FAF= 0.00012413.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0005428292259255238, 10/18422 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.022%
· 353 / 1,614,074
1 hom · FAF 0.026%
1 hom · FAF 0.026%
European (non-Finnish) 333 / 1,179,970 |
0.028% |
Remaining individuals 10 / 62,506 |
0.016% 1 hom |
African/African American 6 / 75,048 |
0.008% |
Admixed American 2 / 60,022 |
0.0033% |
European (Finnish) 1 / 64,038 |
0.0016% |
South Asian 1 / 91,086 |
0.0011% |
+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0089%
· 25 / 280,544
0 hom · FAF 0.012%
0 hom · FAF 0.012%
Remaining individuals 3 / 7,140 |
0.042% |
European (non-Finnish) 22 / 128,432 |
0.017% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian)
gnomAD Canada 🇨🇦
0.054%
· 10 / 18,422
0 hom
0 hom
Remaining individuals 2 / 1,138 |
0.18% |
Latino/Admixed American 1 / 838 |
0.12% |
European (non-Finnish) 7 / 11,742 |
0.06% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, South Asian)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has previously been reported in somatic cancers (COSMIC; COSV104627101, n = 1 times).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 4 PMIDs not cited in assessment
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.
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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR