rs121913673

Positions:

• chr7-116782048-C-A
• chr7-116782048-C-G
• chr7-116782048-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The ENST00000397752.8(MET):​c.3583C>A​(p.Leu1195Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1195V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET ENST00000397752.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.15

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 8 ACMG points.

• PM1: In a helix (size 19) in uniprot entity MET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in ENST00000397752.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-116782048-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13886.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3583C>A	p.Leu1195Ile	missense_variant	18/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3637C>A	p.Leu1213Ile	missense_variant	18/21		NP_001120972.1
MET	NM_001324402.2	c.2293C>A	p.Leu765Ile	missense_variant	17/20		NP_001311331.1
MET	XM_011516223.2	c.3640C>A	p.Leu1214Ile	missense_variant	19/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3583C>A	p.Leu1195Ile	missense_variant	18/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3637C>A	p.Leu1213Ile	missense_variant	18/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*1188C>A		3_prime_UTR_variant, NMD_transcript_variant	17/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;N
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.78
MutPred		0.86		Gain of methylation at K1198 (P = 0.0842);.;
MVP		0.86
MPC		1.9
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.83

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116422102; COSMIC: COSV59263292;