Variant classification summary

NM_000245.4:c.3028+1G>T

MET · NP_000236.2:p.? · NM_000245.4

GRCh37: chr7:116412044 G>T · GRCh38: chr7:116771990 G>T

Gene: MET Transcript: NM_000245.4

Final call

Likely Pathogenic

PS3 strong PP3 moderate PM2 supporting PP1 supporting

Variant details

Gene

MET

Transcript

NM_000245.4

Protein

NP_000236.2:p.?

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 Strong demonstrates abnormal MET exon 14 splicing and damaging functional effects.

2

Pathogenic evidence: PP3 Moderate is supported by a SpliceAI maximum delta of 0.943.

3

Pathogenic evidence: PM2 Supporting is supported by absence from gnomAD v2.1 and v4.1.

4

Pathogenic evidence: PP1 Supporting is supported by segregation in affected members of multiple families.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong, one Moderate, and two Supporting pathogenic criteria satisfy the Likely Pathogenic combination rule; no benign rule is satisfied.

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	Not met	Not met: RT-PCR showed exon 14 skipping with an in-frame 47-amino-acid deletion and MET stabilization, not a demonstrated null loss-of-function product.	PMID:26637977
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo occurrence with both maternity and paternity confirmed is available for this familial variant.
PS3	Met	Met: RT-PCR showed c.3028+1G>T causes MET exon 14 skipping, producing a Δ47-amino-acid receptor with impaired CBL-mediated destabilization and reduced osteogenic function.	PMID:26637977
PS4	Not assessed	Not assessed: the available report lacks unrelated controls and an OR/95% CI, while two PS4 candidate papers remain unavailable for verification.	PMID:26637977
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the PM2 threshold of <=0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: affected carriers were reported, but no pathogenic variant in trans, parental or offspring testing, or phase information was provided.	PMID:26637977
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no assumed de novo occurrence is reported, and the available evidence instead describes familial segregation.
PP1	Met	Met at supporting: the exact variant segregated with osteofibrous dysplasia in six penetrant carriers in family 2 and two in family 3.	PMID:26637977
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
PP3	Met	Met at moderate strength: SpliceAI max delta 0.943 exceeds the >=0.5 PP3 threshold for intronic variants.	spliceai
PP4	Not met	Not met: osteofibrous dysplasia has characteristic lesions but is typically sporadic and has both germline and somatic etiologies.	PMID:26637977
PP5	Not met	Not met: no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.	clinvar PMID:26637977
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the >=0.05 allele frequency required for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF reaching the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: population records show absence but provide no identified healthy adult carrier, zygosity, age, phenotype, or penetrance data.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: the variant causes exon 14 skipping and the resulting METΔ14 receptor resists CBL-mediated destabilization rather than showing normal function or splicing.	PMID:26637977
BS4	Not met	Not met: affected-family segregation is reported, while four non-penetrant carriers were unaffected rather than affected non-segregating members.	PMID:26637977
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a canonical splice-site variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no pathogenic variant in cis or trans was documented, and a fully penetrant dominant MET disorder was not established.	PMID:26637977
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a canonical splice-site variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.943 is above the <=0.1 BP4 threshold, indicating predicted splice impact.	spliceai
BP5	Not met	Not met: affected cases carrying the variant are reported, but no alternate molecular basis for their disease is documented.	PMID:26637977
BP6	Not met	Not met: no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a canonical splice-site variant.	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.