chr7-116759077-G-A

Variant names:

• chr7-116759077-G-A
• rs10215153
• NM_000245.4:c.2265-314G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000245.4(MET):​c.2265-314G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.313 in 151,916 control chromosomes in the GnomAD database, including 7,802 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7802 hom., cov: 33)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.14
• Publications: 11 publications found

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]

MET Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-116759077-G-A is Benign according to our data. Variant chr7-116759077-G-A is described in ClinVar as Benign. ClinVar VariationId is 1183625.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.2265-314G>A		intron_variant	Intron 9 of 20	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2265-314G>A		intron_variant	Intron 9 of 20	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.2265-260G>A		intron_variant	Intron 9 of 20	1		ENSP00000317272.6
MET	ENST00000436117.3	n.2264+457G>A		intron_variant	Intron 9 of 19	1		ENSP00000410980.2
MET	ENST00000422097.2	c.2265-314G>A		intron_variant	Intron 9 of 11	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47482 AN: 151798 Hom.: 7796 Cov.: 33

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.340

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.311

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.313 AC: 47530 AN: 151916 Hom.: 7802 Cov.: 33 AF XY: 0.308 AC XY: 22848 AN XY: 74246

African (AFR) AF: 0.382 AC: 15835 AN: 41404

American (AMR) AF: 0.264 AC: 4027 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 908 AN: 3466

East Asian (EAS) AF: 0.0999 AC: 518 AN: 5184

South Asian (SAS) AF: 0.166 AC: 800 AN: 4812

European-Finnish (FIN) AF: 0.289 AC: 3041 AN: 10530

Middle Eastern (MID) AF: 0.355 AC: 103 AN: 290

European-Non Finnish (NFE) AF: 0.314 AC: 21366 AN: 67940

Other (OTH) AF: 0.312 AC: 657 AN: 2108

Alfa AF: 0.313 Hom.: 13003

Bravo AF: 0.317

Asia WGS AF: 0.137 AC: 478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.0040
DANN	Benign	0.53
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10215153; hg19: chr7-116399131; COSMIC: COSV100577600;