rs35284565

Variant names:

• chr7-116699738-G-A
• rs35284565
• NM_000245.4:c.654G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116699738-G-A
• chr7-116699738-G-C
• chr7-116699738-G-T

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.654G>A​(p.Arg218Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,614,088 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R218R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (3 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.826
• Publications: 6 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]

COMETT (HGNC:51196): (cytosolic oncogenic antisense to MET transcript) This gene encodes a natural antisense transcript highly expressed in papillary thyroid carcinomas harboring BRAF V600E mutation or RET gene rearrangements. This lncRNA induces the downstream MAPK pathway and is part of a co-expression network including different oncogenes belonging to the MAPK and PI3H/AKT pathways. In thyroid carcinomas, this gene has oncogenic properties associated with increased proliferation and drug resistance. [provided by RefSeq, Jan 2020]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 7-116699738-G-A is Benign according to our data. Variant chr7-116699738-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.826 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00139 (211/152290) while in subpopulation AFR AF = 0.00491 (204/41568). AF 95% confidence interval is 0.00436. There are 0 homozygotes in GnomAd4. There are 94 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.654G>A	p.Arg218Arg	synonymous	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.654G>A	p.Arg218Arg	synonymous	Exon 2 of 21	NP_001120972.1
	MET	NM_001324401.3		c.654G>A	p.Arg218Arg	synonymous	Exon 2 of 12	NP_001311330.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.654G>A	p.Arg218Arg	synonymous	Exon 2 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.654G>A	p.Arg218Arg	synonymous	Exon 2 of 21	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.654G>A		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000309 AC: 77 AN: 248858 AF XY: 0.000230

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461798 Hom.: 3 Cov.: 32 AF XY: 0.000114 AC XY: 83 AN XY: 727198

African (AFR) AF: 0.00529 AC: 177 AN: 33466

American (AMR) AF: 0.000246 AC: 11 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111956

Other (OTH) AF: 0.000199 AC: 12 AN: 60390

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74478

African (AFR) AF: 0.00491 AC: 204 AN: 41568

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68008

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.00157

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	not provided (1)
-	-	1	Papillary renal cell carcinoma type 1 (1)
-	-	1	Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma;C4084709:Autosomal recessive nonsyndromic hearing loss 97;C4085248:Osteofibrous dysplasia;C5774205:Arthrogryposis, distal, IIa 11 (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.4
DANN	Benign	0.54
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs35284565; hg19: chr7-116339792;