NM_001127500.3:c.3852+5T>C

MET · NP_001120972.1:p.? · NM_001127500.3

GRCh37: chr7:116423528 T>C · GRCh38: chr7:116783474 T>C

Gene: MET Transcript: NM_001127500.3

Final call

Likely Benign

BP4 supporting BP6 supporting

Variant details

Gene

MET

Transcript

NM_001127500.3

Protein

NP_001120972.1:p.?

gnomAD AF

0.00021870124913727623 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

SpliceAI predicts no significant splice impact (max delta score 0.09), meeting BP4 at the supporting level.

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.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Variant is at the +5 position of the splice donor in intron 19, outside the canonical ±1,2 splice consensus. The PVS1 variant assessment classifies it as bucket 'other' with apply_generic_pvs1_framework=false; SpliceAI predicts no significant splicing impact (max delta 0.09), and no functional data demonstrate a null effect. PVS1 is not applicable.	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	N/A	Intronic variant with no amino acid change; PS1 requires the same amino acid change as a previously established pathogenic variant.
PS2	Not met	No de novo observations with both maternity and paternity confirmed have been identified for this variant in ClinVar or published literature.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed for this specific variant. SpliceAI predicts no significant splice impact (max delta 0.09), but computational prediction alone does not satisfy PS3 requirements for functional evidence of a deleterious effect.	spliceai
PS4	Not met	No published case-control studies demonstrate statistically significant enrichment of this variant in affected individuals versus controls. The variant is present in gnomAD at low frequency but without disease association data.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	This variant has not been classified as pathogenic by a reputable source. ClinVar consensus classification is Likely benign (5 clinical laboratories) with 2 laboratories reporting Uncertain significance. PS5 requires a reputable source to have recently reported the variant as pathogenic.	clinvar
PM1	Not met	Located in intron 19 of MET; there is no evidence that this splice donor region is a recognized mutational hotspot or a critical functional domain without benign variation in MET.
PM2	Not met	Present in gnomAD v4.1 at 0.022% (353/1,614,074 alleles) with 1 homozygote and in v2.1 at 0.0089% (25/280,544 alleles). The allele count and homozygote observation in v4.1 are inconsistent with an ultra-rare pathogenic variant in a dominantly inherited cancer predisposition gene, even though the overall frequency is below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	Intronic variant with no amino acid residue; classic same-residue PM5 semantics cannot be applied. PM5 candidates confirms ineligible.	pm5_candidates
PM6	Not met	No de novo observations without confirmation of maternity and paternity have been reported for this variant.	clinvar
PP1	Not met	No co-segregation data in multiple affected family members has been reported for this variant.
PP2	N/A	Intronic variant; PP2 applies only to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta 0.09). REVEL and BayesDel scores are not available for this intronic variant.	spliceai
PP4	Not met	No patient phenotype or family history data were provided for this case; cannot evaluate whether the phenotype is highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. ClinVar aggregate classification is Likely benign (5 clinical laboratories) with 2 laboratories reporting Uncertain significance. The cited ClinVar PMIDs (25741868, 28492532) are methodology guideline papers that do not mention this specific variant.	clinvar
BA1	Not met	Highest population allele frequency is 0.022% (gnomAD v4.1), well below the >1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Highest population allele frequency is 0.022% (gnomAD v4.1) and highest subpopulation AF is 0.042% (gnomAD v2.1 OTH), both below the >0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No confirmed observation of this variant in healthy adult individuals for a fully penetrant early-onset disorder has been reported. The gnomAD homozygote observation (v4.1, n=1) lacks phenotypic confirmation.	gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this specific variant. SpliceAI prediction (max delta 0.09) is computational only and does not constitute experimental functional evidence.	spliceai
BS4	Not met	No segregation data in affected family members demonstrating lack of co-segregation with disease has been reported.
BP1	N/A	Intronic variant; BP1 applies only to missense variants in genes where primarily truncating variants cause disease.
BP2	Not met	No observation of this variant in cis with a pathogenic MET variant has been reported.
BP3	N/A	Variant is a substitution; BP3 applies only to in-frame deletions or insertions in repetitive regions.
BP4	Met	SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09). Multiple computational lines of evidence suggest no impact on splicing.	spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Met	This variant is classified as Likely benign by multiple clinical laboratories in ClinVar (5 laboratories: GeneDx, Ambry Genetics, Labcorp/Invitae, Myriad Genetics, PreventionGenetics). The aggregate ClinVar classification is Likely benign with criteria provided by single submitters.	clinvar
BP7	N/A	Intronic variant located at +5 of the splice donor; BP7 applies only to synonymous variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.