Variant classification summary

NM_001127500.2:c.3082G>C

MET · NP_001120972.1:p.(Asp1028His) · NM_001127500.2

GRCh37: chr7:116412043 G>C · GRCh38: chr7:116771989 G>C

Gene: MET Transcript: NM_001127500.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

MET

Transcript

NM_001127500.2

Protein

NP_001120972.1:p.(Asp1028His)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

PP3 (Supporting): SpliceAI predicts splice-donor loss at the annotated donor position (max delta 0.925, above the 0.8 high-precision tier).

3

Final classification: VUS — under generic ACMG/AMP 2015 rules, two supporting criteria (PM2 and PP3) do not combine to pathogenic or benign.

Final determination:

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	Not applicable: c.3082G>C is a missense substitution, not a null variant class covered by PVS1.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical p.Asp1028His change via a different nucleotide was found.	clinvar
PS2	Not assessed	Not assessed: no parental testing or genotype data were available to evaluate a possible de novo occurrence.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional assay data (kinase, splicing, or cell-based) for this variant were available.
PS4	Not assessed	Not assessed: no germline case-control cohort or enrichment statistic was available for this variant.
PM1	Not assessed	Not assessed: no germline mutational-hotspot or critical-domain annotation for residue 1028 was available.
PM2	Met	Met (Supporting): allele absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected-proband, segregation, or trans-phase data were available.
PM4	N/A	Not applicable: missense substitution causes no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no pathogenic missense change at codon 1028 was identified for comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no documented unconfirmed de novo occurrence was available.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no familial segregation data were available for this variant.	generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no MET missense-constraint metric or curated benign-missense-rate data were available.
PP3	Met	Met (Supporting): SpliceAI predicts splice-donor loss at the donor position itself (max delta 0.925, above the 0.8 high-precision cutoff).	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnosis was provided.
PP5	Not met	Not met: ClinVar has no record for this exact variant and no expert-panel pathogenic classification.	clinvar
BA1	Not met	Not met: allele is absent from gnomAD, so no population frequency approaches the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, so no elevated allele frequency supports BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations of the variant in healthy adults or unaffected individuals were documented.
BS3	Not assessed	Not assessed: no functional assay evidence showing normal protein function was available.
BS4	Not assessed	Not assessed: no affected individual lacking the variant (non-segregation) was documented.	generic_acmg_combination_rules
BP1	Not assessed	Not assessed: no citable evidence that MET disease is primarily caused by truncating variants was available.
BP2	Not assessed	Not assessed: no observations of this variant in trans or in cis with a pathogenic variant were available.
BP3	N/A	Not applicable: missense substitution does not alter protein length in a repetitive region, which BP3 requires.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the dominant in-silico signal (SpliceAI donor loss, max delta 0.925) indicates damage, not a benign effect.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no clinical phenotype or independent alternate molecular basis for disease was provided.
BP6	Not met	Not met: ClinVar has no record for this exact variant and no expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous variants; this is a missense substitution.	generic_acmg_combination_rules

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.