7-116783329-G-T

Variant names:

• chr7-116783329-G-T
• rs121913670
• NM_000245.4:c.3658G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000245.4(MET):​c.3658G>T​(p.Val1220Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1220L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

Genes affected

MET (HGNC:7029): (MET proto-oncogene, receptor tyrosine kinase) This gene encodes a member of the receptor tyrosine kinase family of proteins and the product of the proto-oncogene MET. The encoded preproprotein is proteolytically processed to generate alpha and beta subunits that are linked via disulfide bonds to form the mature receptor. Further processing of the beta subunit results in the formation of the M10 peptide, which has been shown to reduce lung fibrosis. Binding of its ligand, hepatocyte growth factor, induces dimerization and activation of the receptor, which plays a role in cellular survival, embryogenesis, and cellular migration and invasion. Mutations in this gene are associated with papillary renal cell carcinoma, hepatocellular carcinoma, and various head and neck cancers. Amplification and overexpression of this gene are also associated with multiple human cancers. [provided by RefSeq, May 2016]

MET Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-116783329-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3658G>T	p.Val1220Phe	missense_variant	Exon 19 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3712G>T	p.Val1238Phe	missense_variant	Exon 19 of 21		NP_001120972.1
MET	NM_001324402.2	c.2368G>T	p.Val790Phe	missense_variant	Exon 18 of 20		NP_001311331.1
MET	XM_011516223.2	c.3715G>T	p.Val1239Phe	missense_variant	Exon 20 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3658G>T	p.Val1220Phe	missense_variant	Exon 19 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3712G>T	p.Val1238Phe	missense_variant	Exon 19 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1263G>T		non_coding_transcript_exon_variant	Exon 18 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1263G>T		3_prime_UTR_variant	Exon 18 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1238F variant (also known as c.3712G>T), located in coding exon 18 of the MET gene, results from a G to T substitution at nucleotide position 3712. The valine at codon 1238 is replaced by phenylalanine, an amino acid with highly similar properties. Another alteration at the same codon, p.V1238I (c.3712G>A), has been reported multiple probands with MET-associated disease and shown to segregate with disease in at least one family (Schmidt L et al, Nat. Genet. 1997 May; Schmidt L et al, Oncogene 1999 Apr;18(14):2343-50) (16(1):68-73; Prat E et al. Cancer Genet Cytogenet, 2006 Jan;164:142-7). One study examined the functional significance of MET V1238I by transfecting cells with MET mutant cDNA and found that while cells transfected with V1238I were phenotypically normal, they had moderately enhanced kinase activity toward an exogenous substrate when compared with wild-type MET. Further, cells expressing MET V1238I were shown to be tumorigenic in nude mice (Jeffers M et al, Proc. Natl. Acad. Sci. U.S.A. 1997 Oct; 94(21):11445-50). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Benign	0.078	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Pathogenic	3.6	H;.
PhyloP100		10
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.75		Gain of catalytic residue at V1220 (P = 0.0208);.;
MVP		0.81
MPC		2.1
ClinPred		1.0	D
GERP RS		5.5
Varity_R		1.0
gMVP		0.99
Mutation Taster		=9/91	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121913670; hg19: chr7-116423383;