7-116783359-T-C

Variant names:

• chr7-116783359-T-C
• rs121913247
• NM_000245.4:c.3688T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000245.4(MET):​c.3688T>C​(p.Tyr1230His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. Y1230D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a turn (size 3) in uniprot entity MET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3688T>C	p.Tyr1230His	missense_variant	Exon 19 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3742T>C	p.Tyr1248His	missense_variant	Exon 19 of 21		NP_001120972.1
MET	NM_001324402.2	c.2398T>C	p.Tyr800His	missense_variant	Exon 18 of 20		NP_001311331.1
MET	XM_011516223.2	c.3745T>C	p.Tyr1249His	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.3688T>C	p.Tyr1230His	missense_variant	Exon 19 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3742T>C	p.Tyr1248His	missense_variant	Exon 19 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1293T>C		non_coding_transcript_exon_variant	Exon 18 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1293T>C		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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Sep 22, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia;C5774205:Arthrogryposis, distal, IIa 11 Uncertain:1

May 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.63
MutPred		0.69		Gain of disorder (P = 0.0359);.;
MVP		0.85
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.86

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

Publications

LitVar

Other links and lift over

dbSNP: rs121913247; hg19: chr7-116423413; COSMIC: COSV59256836;