chr7-116775069-C-A

Position:

• chr7-116775069-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000397752.8(MET):​c.3217C>A​(p.Pro1073Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. P1073L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET ENST00000397752.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.17

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34398794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3217C>A	p.Pro1073Thr	missense_variant	15/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3271C>A	p.Pro1091Thr	missense_variant	15/21		NP_001120972.1
MET	NM_001324402.2	c.1927C>A	p.Pro643Thr	missense_variant	14/20		NP_001311331.1
MET	XM_011516223.2	c.3274C>A	p.Pro1092Thr	missense_variant	16/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3217C>A	p.Pro1073Thr	missense_variant	15/21	1	NM_000245.4	ENSP00000380860	P3
MET	ENST00000318493.11	c.3271C>A	p.Pro1091Thr	missense_variant	15/21	1		ENSP00000317272	A2
MET	ENST00000436117.3	c.*822C>A		3_prime_UTR_variant, NMD_transcript_variant	14/20	1		ENSP00000410980
MET	ENST00000454623.1	c.472C>A	p.Pro158Thr	missense_variant	3/3	5		ENSP00000398140

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 20, 2022

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MET protein function. This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1091 of the MET protein (p.Pro1091Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.6	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N;N;D
REVEL	Benign	0.20
Sift	Benign	0.047	D;D;D
Sift4G	Benign	0.27	T;T;D
Polyphen		0.46	P;B;.
Vest4		0.31
MutPred		0.28		Gain of loop (P = 0.2754);.;.;
MVP		0.47
MPC		0.94
ClinPred		0.89	D
GERP RS		5.6
Varity_R		0.48
gMVP		0.53

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: chr7-116415123;