7-116741100-T-G

Variant names:

• chr7-116741100-T-G
• rs553431706
• NM_000245.4:c.1701+75T>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000245.4(MET):​c.1701+75T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,545,022 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 31)
  • Exomes 𝑓: 0.0062 (36 hom.)
• Consequence: MET NM_000245.4 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.0670
• Publications: 0 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00386 (583/150894) while in subpopulation NFE AF = 0.00669 (453/67672). AF 95% confidence interval is 0.00618. There are 4 homozygotes in GnomAd4. There are 261 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.1701+75T>G		intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.1701+75T>G		intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.411+75T>G		intron	N/A	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.1701+75T>G		intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.1701+75T>G		intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.1701+75T>G		intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 583 AN: 150780 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00172

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00202

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00669

Gnomad OTH AF: 0.00242

GnomAD2 exomes AF: 0.00430 AC: 847 AN: 197196 AF XY: 0.00443

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.000932

Gnomad ASJ exome AF: 0.00355

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00173

Gnomad NFE exome AF: 0.00801

Gnomad OTH exome AF: 0.00633

GnomAD4 exome AF: 0.00620 AC: 8644 AN: 1394128 Hom.: 36 Cov.: 24 AF XY: 0.00602 AC XY: 4180 AN XY: 693942

African (AFR) AF: 0.00126 AC: 39 AN: 30926

American (AMR) AF: 0.00130 AC: 50 AN: 38432

Ashkenazi Jewish (ASJ) AF: 0.00359 AC: 90 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39124

South Asian (SAS) AF: 0.000139 AC: 11 AN: 79070

European-Finnish (FIN) AF: 0.00226 AC: 108 AN: 47784

Middle Eastern (MID) AF: 0.00110 AC: 6 AN: 5476

European-Non Finnish (NFE) AF: 0.00757 AC: 8101 AN: 1070368

Other (OTH) AF: 0.00413 AC: 239 AN: 57850

GnomAD4 genome AF: 0.00386 AC: 583 AN: 150894 Hom.: 4 Cov.: 31 AF XY: 0.00354 AC XY: 261 AN XY: 73696

African (AFR) AF: 0.00136 AC: 56 AN: 41026

American (AMR) AF: 0.00172 AC: 26 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00202 AC: 21 AN: 10412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00669 AC: 453 AN: 67672

Other (OTH) AF: 0.00239 AC: 5 AN: 2088

Alfa AF: 0.00558 Hom.: 1

Bravo AF: 0.00392

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.66
DANN	Benign	0.44
PhyloP100		0.067
Mutation Taster		=100/0	polymorphism

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: rs553431706; hg19: chr7-116381154; COSMIC: COSV59258063;