7-116700032-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000245.4(MET):c.948A>G(p.Ile316Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,614,038 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I316T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0058 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00089 (8 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:12 O:1
• Conservation: PhyloP100: -0.432

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011562258).
• BP6: Variant 7-116700032-A-G is Benign according to our data. Variant chr7-116700032-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 41629.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-116700032-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00578 (881/152320) while in subpopulation AFR AF= 0.0193 (803/41572). AF 95% confidence interval is 0.0182. There are 8 homozygotes in gnomad4. There are 439 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MET	NM_000245.4	c.948A>G	p.Ile316Met	missense_variant	2/21	ENST00000397752.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MET	ENST00000397752.8	c.948A>G	p.Ile316Met	missense_variant	2/21	1	NM_000245.4	P3
MET	ENST00000318493.11	c.948A>G	p.Ile316Met	missense_variant	2/21	1		A2
MET	ENST00000436117.3	c.948A>G	p.Ile316Met	missense_variant, NMD_transcript_variant	2/20	1
MET	ENST00000422097.2	c.948A>G	p.Ile316Met	missense_variant	2/12	3

Frequencies

GnomAD3 genomes AF: 0.00577 AC: 878 AN: 152202 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00163 AC: 405 AN: 248850 Hom.: 0 AF XY: 0.00145 AC XY: 196 AN XY: 135006

Gnomad AFR exome AF: 0.0188

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000888 AC: 1298 AN: 1461718 Hom.: 8 Cov.: 32 AF XY: 0.000809 AC XY: 588 AN XY: 727160

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00199

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000270

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00578 AC: 881 AN: 152320 Hom.: 8 Cov.: 32 AF XY: 0.00589 AC XY: 439 AN XY: 74488

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00659

ESP6500AA AF: 0.0193 AC: 72

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.00177 AC: 214

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2012	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2021	Variant summary: MET c.948A>G (p.Ile316Met) results in a conservative amino acid change located in the Sema domain (IPR001627) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248850 control chromosomes. The observed variant frequency is approximately 1085 fold of the estimated maximal expected allele frequency for a pathogenic variant in MET causing Papillary Renal Cell Carcinoma phenotype (1.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.948A>G in individuals affected with Papillary Renal Cell Carcinoma and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MET: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2018	This variant is associated with the following publications: (PMID: 21904579, 24728327, 31801140) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 29, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 12, 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. -

Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 31, 2022

- -

Renal cell carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Papillary renal cell carcinoma type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.;.
Eigen	Benign	0.0062
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.7	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0060	D;D;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		0.84	P;P;.
Vest4		0.57
MVP		0.32
MPC		0.78
ClinPred		0.056	T
GERP RS		-1.4
Varity_R		0.28
gMVP		0.41

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: rs35225896; hg19: chr7-116340086; COSMIC: COSV104403516; COSMIC: COSV104403516;