7-116769637-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_000245.4(MET):​c.2584-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 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 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MET NM_000245.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001014
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-116769637-C-T is Benign according to our data. Variant chr7-116769637-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 517049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.2584-8C>T		splice_region intron	N/A	NP_000236.2
	MET	NM_001127500.3		c.2638-8C>T		splice_region intron	N/A	NP_001120972.1
	MET	NM_001324402.2		c.1294-8C>T		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>T		splice_region intron	N/A	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.2638-8C>T		splice_region intron	N/A	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*189-8C>T		splice_region intron	N/A	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 141 AN: 133886 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00767

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000855

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00883 AC: 1811 AN: 205052 AF XY: 0.00898

Gnomad AFR exome AF: 0.00346

Gnomad AMR exome AF: 0.0146

Gnomad ASJ exome AF: 0.0106

Gnomad EAS exome AF: 0.00867

Gnomad FIN exome AF: 0.00123

Gnomad NFE exome AF: 0.00599

Gnomad OTH exome AF: 0.0102

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00150 AC: 2095 AN: 1396732 Hom.: 0 Cov.: 35 AF XY: 0.00153 AC XY: 1061 AN XY: 693700

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

African (AFR) AF: 0.00629 AC: 190 AN: 30204

American (AMR) AF: 0.0142 AC: 502 AN: 35406

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 81 AN: 22964

East Asian (EAS) AF: 0.000238 AC: 9 AN: 37744

South Asian (SAS) AF: 0.00731 AC: 555 AN: 75970

European-Finnish (FIN) AF: 0.000542 AC: 27 AN: 49820

Middle Eastern (MID) AF: 0.00187 AC: 10 AN: 5360

European-Non Finnish (NFE) AF: 0.000577 AC: 624 AN: 1082256

Other (OTH) AF: 0.00170 AC: 97 AN: 57008

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.00107 AC: 143 AN: 133956 Hom.: 0 Cov.: 31 AF XY: 0.00113 AC XY: 73 AN XY: 64658

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

African (AFR) AF: 0.000502 AC: 18 AN: 35826

American (AMR) AF: 0.000888 AC: 12 AN: 13506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3012

East Asian (EAS) AF: 0.00 AC: 0 AN: 4662

South Asian (SAS) AF: 0.00 AC: 0 AN: 4224

European-Finnish (FIN) AF: 0.00767 AC: 60 AN: 7824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 256

European-Non Finnish (NFE) AF: 0.000855 AC: 53 AN: 61974

Other (OTH) AF: 0.00 AC: 0 AN: 1860

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00106 Hom.: 2

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Papillary renal cell carcinoma type 1 (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.089
DANN	Benign	0.39
PhyloP100		-0.36
PromoterAI		-0.029	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.046
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;