7-116796011-G-A

Position:

• chr7-116796011-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1 BP4_Strong

The NM_000245.4(MET):​c.4060G>A​(p.Ala1354Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 2.09

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_benign. Variant got -2 ACMG points.

• PM1: In a region_of_interest Interaction with RANBP9 (size 178) in uniprot entity MET_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000245.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.050646126).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.4060G>A	p.Ala1354Thr	missense_variant	21/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.4114G>A	p.Ala1372Thr	missense_variant	21/21		NP_001120972.1
MET	NM_001324402.2	c.2770G>A	p.Ala924Thr	missense_variant	20/20		NP_001311331.1
MET	XM_011516223.2	c.4117G>A	p.Ala1373Thr	missense_variant	22/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.4060G>A	p.Ala1354Thr	missense_variant	21/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.4114G>A	p.Ala1372Thr	missense_variant	21/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*1665G>A		3_prime_UTR_variant, NMD_transcript_variant	20/20	1		ENSP00000410980

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249306 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461698 Hom.: 0 Cov.: 57 AF XY: 0.00000825 AC XY: 6 AN XY: 727158

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 97 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 13, 2023

- -

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2022

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1372 of the MET protein (p.Ala1372Thr). This variant is present in population databases (rs761522694, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of MET-related disease. (Invitae). ClinVar contains an entry for this variant (Variation ID: 524851). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 19, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with congenital diaphragmatic hernia (Longoni et al., 2014); This variant is associated with the following publications: (PMID: 25107291) -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.70	N;.
MutationTaster	Benign	0.95	D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.10
Sift	Benign	0.44	T;T
Sift4G	Benign	0.47	T;T
Polyphen		0.0020	B;B
Vest4		0.13
MutPred		0.40		Gain of glycosylation at A1354 (P = 0.0253);.;
MVP		0.38
MPC		0.76
ClinPred		0.072	T
GERP RS		2.9
Varity_R		0.19
gMVP		0.61

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: rs761522694; hg19: chr7-116436065;