rs587780736

Variant names:

• chr7-116769636-TC-T
• rs587780736
• NM_000245.4:c.2584-7delC

Your query was ambiguous. Multiple possible variants found:

• chr7-116769636-TC-T
• chr7-116769636-TC-TCC
• chr7-116769636-TC-TCCC

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000245.4(MET):​c.2584-7delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,600,862 control chromosomes in the GnomAD database, including 4 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (3 hom.)
• Consequence: MET NM_000245.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -0.358
• Publications: 1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: 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.

• BP6: Variant 7-116769636-TC-T is Benign according to our data. Variant chr7-116769636-TC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194024.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00132 (192/145166) while in subpopulation NFE AF = 0.000835 (55/65846). AF 95% confidence interval is 0.000659. There are 1 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.2584-7delC		splice_region intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.2638-7delC		splice_region intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.1294-7delC		splice_region intron	N/A	NP_001311331.1	B4DLF5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.2584-8delC		splice_region intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.2638-8delC		splice_region intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.*189-8delC		splice_region intron	N/A	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.00132 AC: 192 AN: 145050 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000755

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.000416

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.000835

Gnomad OTH AF: 0.00202

GnomAD2 exomes AF: 0.00157 AC: 377 AN: 239374 AF XY: 0.00155

Gnomad AFR exome AF: 0.000601

Gnomad AMR exome AF: 0.000743

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.0000578

Gnomad FIN exome AF: 0.000191

Gnomad NFE exome AF: 0.000889

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00105 AC: 1531 AN: 1455696 Hom.: 3 Cov.: 35 AF XY: 0.00105 AC XY: 757 AN XY: 724364

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00145 AC: 48 AN: 33072

American (AMR) AF: 0.00205 AC: 90 AN: 43960

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 679 AN: 25668

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.000373 AC: 32 AN: 85814

European-Finnish (FIN) AF: 0.000113 AC: 6 AN: 52966

Middle Eastern (MID) AF: 0.00612 AC: 35 AN: 5722

European-Non Finnish (NFE) AF: 0.000434 AC: 481 AN: 1108766

Other (OTH) AF: 0.00265 AC: 159 AN: 60078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00132 AC: 192 AN: 145166 Hom.: 1 Cov.: 31 AF XY: 0.00127 AC XY: 90 AN XY: 70714

African (AFR) AF: 0.000181 AC: 7 AN: 38758

American (AMR) AF: 0.000754 AC: 11 AN: 14584

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 105 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4656

European-Finnish (FIN) AF: 0.000416 AC: 4 AN: 9626

Middle Eastern (MID) AF: 0.0179 AC: 5 AN: 280

European-Non Finnish (NFE) AF: 0.000835 AC: 55 AN: 65846

Other (OTH) AF: 0.00200 AC: 4 AN: 1998

Alfa AF: 0.00117 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	1	1	not provided (2)
-	-	2	Papillary renal cell carcinoma type 1 (2)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Nonsyndromic genetic hearing loss (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587780736; hg19: chr7-116409690; COSMIC: COSV104403447;