rs146651797

Variant names:

• chr7-116778957-T-C
• rs146651797
• NM_000245.4:c.3522T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-116778957-T-C
• chr7-116778957-T-A
• chr7-116778957-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000245.4(MET):​c.3522T>C​(p.His1174His) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,613,674 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.0022 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: MET NM_000245.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.00005833
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -1.38
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 7-116778957-T-C is Benign according to our data. Variant chr7-116778957-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134645.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00218 (332/152336) while in subpopulation AFR AF = 0.00762 (317/41580). AF 95% confidence interval is 0.00693. There are 3 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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.3522T>C	p.His1174His	splice_region synonymous	Exon 17 of 21	NP_000236.2
	MET	NM_001127500.3		c.3576T>C	p.His1192His	splice_region synonymous	Exon 17 of 21	NP_001120972.1	P08581-2
	MET	NM_001324402.2		c.2232T>C	p.His744His	splice_region synonymous	Exon 16 of 20	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.3522T>C	p.His1174His	splice_region synonymous	Exon 17 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.3576T>C	p.His1192His	splice_region synonymous	Exon 17 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.*1127T>C		splice_region non_coding_transcript_exon	Exon 16 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.00219 AC: 333 AN: 152218 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000623 AC: 155 AN: 248840 AF XY: 0.000459

Gnomad AFR exome AF: 0.00814

Gnomad AMR exome AF: 0.000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000253 AC: 370 AN: 1461338 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 726978

African (AFR) AF: 0.00846 AC: 283 AN: 33458

American (AMR) AF: 0.000581 AC: 26 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5524

European-Non Finnish (NFE) AF: 0.0000279 AC: 31 AN: 1111860

Other (OTH) AF: 0.000480 AC: 29 AN: 60356

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152336 Hom.: 3 Cov.: 32 AF XY: 0.00208 AC XY: 155 AN XY: 74504

African (AFR) AF: 0.00762 AC: 317 AN: 41580

American (AMR) AF: 0.000523 AC: 8 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000871 Hom.: 0

Bravo AF: 0.00252

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	2	not specified (3)
-	-	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	-0.75
CADD	Benign	0.064
DANN	Benign	0.59
PhyloP100		-1.4
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000058
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: rs146651797; hg19: chr7-116419011;