rs755234697

Positions:

• chr7-116778787-A-C
• chr7-116778787-A-G
• chr7-116778787-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000245.4(MET):​c.3352A>C​(p.Ile1118Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29

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 2 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity MET_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07968414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3352A>C	p.Ile1118Leu	missense_variant	17/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3406A>C	p.Ile1136Leu	missense_variant	17/21		NP_001120972.1
MET	NM_001324402.2	c.2062A>C	p.Ile688Leu	missense_variant	16/20		NP_001311331.1
MET	XM_011516223.2	c.3409A>C	p.Ile1137Leu	missense_variant	18/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3352A>C	p.Ile1118Leu	missense_variant	17/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3406A>C	p.Ile1136Leu	missense_variant	17/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*957A>C		non_coding_transcript_exon_variant	16/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*957A>C		3_prime_UTR_variant	16/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74384

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Uncertain	0.43	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.84	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-0.010	N;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.21	N;N
REVEL	Benign	0.23
Sift	Benign	0.52	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.0	B;B
Vest4		0.29
MutPred		0.34		Gain of helix (P = 0.1736);.;
MVP		0.37
MPC		0.25
ClinPred		0.20	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.42

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: rs755234697; hg19: chr7-116418841;