chr7-116769637-C-G

Variant names:

• chr7-116769637-C-G
• rs370833501
• NM_000245.4:c.2584-8C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_000245.4(MET):​c.2584-8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,532,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000037 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: MET NM_000245.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002460
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.358
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-116769637-C-G is Benign according to our data. Variant chr7-116769637-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 246631.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000373 (5/134160) while in subpopulation AFR AF = 0.00014 (5/35770). AF 95% confidence interval is 0.0000545. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.2584-8C>G		splice_region intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.2638-8C>G		splice_region intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.1294-8C>G		splice_region 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.2584-8C>G		splice_region intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.2638-8C>G		splice_region intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*189-8C>G		splice_region intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.0000373 AC: 5 AN: 134160 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000140

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: 0.00000488 AC: 1 AN: 205052 AF XY: 0.00000890

Gnomad AFR exome AF: 0.0000752

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: 0.00000358 AC: 5 AN: 1398456 Hom.: 0 Cov.: 35 AF XY: 0.00000432 AC XY: 3 AN XY: 694530

African (AFR) AF: 0.0000657 AC: 2 AN: 30426

American (AMR) AF: 0.00 AC: 0 AN: 35774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23032

East Asian (EAS) AF: 0.00 AC: 0 AN: 37762

South Asian (SAS) AF: 0.00 AC: 0 AN: 76294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 0.00000277 AC: 3 AN: 1082778

Other (OTH) AF: 0.00 AC: 0 AN: 57098

GnomAD4 genome AF: 0.0000373 AC: 5 AN: 134160 Hom.: 0 Cov.: 31 AF XY: 0.0000309 AC XY: 2 AN XY: 64702

African (AFR) AF: 0.000140 AC: 5 AN: 35770

American (AMR) AF: 0.00 AC: 0 AN: 13496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3018

East Asian (EAS) AF: 0.00 AC: 0 AN: 4678

South Asian (SAS) AF: 0.00 AC: 0 AN: 4238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7928

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62092

Other (OTH) AF: 0.00 AC: 0 AN: 1844

Alfa AF: 0.00 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.083
DANN	Benign	0.44
PhyloP100		-0.36
PromoterAI		-0.012	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.020
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: rs370833501; hg19: chr7-116409691;