rs41737

Positions:

• chr7-116796043-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000245.4(MET):​c.4092G>A​(p.Pro1364Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.436 in 1,613,794 control chromosomes in the GnomAD database, including 158,361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11157 hom., cov: 32)
  • Exomes 𝑓: 0.44 (147204 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.06

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 7-116796043-G-A is Benign according to our data. Variant chr7-116796043-G-A is described in ClinVar as [Benign]. Clinvar id is 93576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116796043-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.06 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.4092G>A	p.Pro1364Pro	synonymous_variant	21/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.4146G>A	p.Pro1382Pro	synonymous_variant	21/21		NP_001120972.1
MET	NM_001324402.2	c.2802G>A	p.Pro934Pro	synonymous_variant	20/20		NP_001311331.1
MET	XM_011516223.2	c.4149G>A	p.Pro1383Pro	synonymous_variant	22/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.4092G>A	p.Pro1364Pro	synonymous_variant	21/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.4146G>A	p.Pro1382Pro	synonymous_variant	21/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1697G>A		non_coding_transcript_exon_variant	20/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1697G>A		3_prime_UTR_variant	20/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53319 AN: 151892 Hom.: 11170 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.435 AC: 108397 AN: 249274 Hom.: 24780 AF XY: 0.437 AC XY: 59126 AN XY: 135226

Gnomad AFR exome AF: 0.0920

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.487

Gnomad EAS exome AF: 0.459

Gnomad SAS exome AF: 0.460

Gnomad FIN exome AF: 0.394

Gnomad NFE exome AF: 0.447

Gnomad OTH exome AF: 0.457

GnomAD4 exome AF: 0.444 AC: 649708 AN: 1461784 Hom.: 147204 Cov.: 60 AF XY: 0.446 AC XY: 324023 AN XY: 727194

Gnomad4 AFR exome AF: 0.0895

Gnomad4 AMR exome AF: 0.511

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.490

Gnomad4 SAS exome AF: 0.455

Gnomad4 FIN exome AF: 0.399

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.441

GnomAD4 genome AF: 0.351 AC: 53295 AN: 152010 Hom.: 11157 Cov.: 32 AF XY: 0.353 AC XY: 26216 AN XY: 74284

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.456

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.387

Alfa AF: 0.433 Hom.: 29496

Bravo AF: 0.346

Asia WGS AF: 0.415 AC: 1444 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.450

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2014	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2016	Variant summary: The MET c.4146G>A (p.Pro1382Pro) variant causes a synonymous change involving a non-conserved nucleotide with 5/5 splice prediction tools predicting no significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 51284/120730 (1/ no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of ***. However, these predictions have yet to be confirmed by functional studies. This variant was found in 51284/120730 control chromosomes (1/2, 11610 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic MET variant of 1/666666. In addition, multiple reputable clinical laboratories cite the variant as "benign." Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Papillary renal cell carcinoma type 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Autosomal recessive nonsyndromic hearing loss 97 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

This alteration is classified as 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
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.40
DANN	Benign	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: rs41737; hg19: chr7-116436097; COSMIC: COSV59255944;