7-116769636-TC-TCCC

Variant names:

• chr7-116769636-T-TCC
• rs587780736
• NM_000245.4:c.2584-8_2584-7dupCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP6_Moderate

The NM_000245.4(MET):​c.2584-8_2584-7dupCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,601,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000069 (0 hom., cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MET NM_000245.4 splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-116769636-T-TCC is Benign according to our data. Variant chr7-116769636-T-TCC is described in ClinVar as Likely_benign. ClinVar VariationId is 3773321.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2584-8_2584-7dupCC		splice_region intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.2638-8_2638-7dupCC		splice_region intron	N/A	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.1294-8_1294-7dupCC		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.2584-9_2584-8insCC		splice_region intron	N/A	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.2638-9_2638-8insCC		splice_region intron	N/A	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.*189-9_*189-8insCC		splice_region intron	N/A	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.00000689 AC: 1 AN: 145078 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000259

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000418 AC: 1 AN: 239374 AF XY: 0.00

Gnomad AFR exome AF: 0.0000668

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456134 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724562

African (AFR) AF: 0.0000302 AC: 1 AN: 33094

American (AMR) AF: 0.00 AC: 0 AN: 43996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52978

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108888

Other (OTH) AF: 0.00 AC: 0 AN: 60132

GnomAD4 genome AF: 0.00000689 AC: 1 AN: 145078 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 70606

African (AFR) AF: 0.0000259 AC: 1 AN: 38650

American (AMR) AF: 0.00 AC: 0 AN: 14568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3414

East Asian (EAS) AF: 0.00 AC: 0 AN: 5120

South Asian (SAS) AF: 0.00 AC: 0 AN: 4658

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 300

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65858

Other (OTH) AF: 0.00 AC: 0 AN: 1978

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Papillary renal cell carcinoma type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780736; hg19: chr7-116409690;