rs11762213

Variant names:

• chr7-116699228-G-A
• rs11762213
• NM_000245.4:c.144G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116699228-G-A
• chr7-116699228-G-C
• chr7-116699228-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000245.4(MET):​c.144G>A​(p.Ala48Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 1,613,846 control chromosomes in the GnomAD database, including 1,985 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (108 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1877 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.559
• Publications: 25 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=-0.74).
• BP6: Variant 7-116699228-G-A is Benign according to our data. Variant chr7-116699228-G-A is described in ClinVar as Benign. ClinVar VariationId is 93567.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.559 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0505 is higher than 0.05.

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.144G>A	p.Ala48Ala	synonymous	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.144G>A	p.Ala48Ala	synonymous	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.144G>A	p.Ala48Ala	synonymous	Exon 2 of 12	NP_001311330.1	E6Y365

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.144G>A	p.Ala48Ala	synonymous	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.144G>A	p.Ala48Ala	synonymous	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000456159.1	TSL:1	c.201G>A	p.Ala67Ala	synonymous	Exon 3 of 3	ENSP00000413857.1	C9JKM5

Frequencies

GnomAD3 genomes AF: 0.0331 AC: 5028 AN: 152004 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0114

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0372

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00686

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0519

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0332 AC: 8281 AN: 249368 AF XY: 0.0338

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0305

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0152

Gnomad NFE exome AF: 0.0534

Gnomad OTH exome AF: 0.0389

GnomAD4 exome AF: 0.0469 AC: 68626 AN: 1461724 Hom.: 1877 Cov.: 32 AF XY: 0.0456 AC XY: 33156 AN XY: 727160

African (AFR) AF: 0.00902 AC: 302 AN: 33468

American (AMR) AF: 0.0265 AC: 1185 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 756 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0108 AC: 931 AN: 86256

European-Finnish (FIN) AF: 0.0152 AC: 814 AN: 53420

Middle Eastern (MID) AF: 0.0206 AC: 119 AN: 5766

European-Non Finnish (NFE) AF: 0.0559 AC: 62130 AN: 1111906

Other (OTH) AF: 0.0395 AC: 2387 AN: 60390

GnomAD4 genome AF: 0.0331 AC: 5028 AN: 152122 Hom.: 108 Cov.: 32 AF XY: 0.0310 AC XY: 2303 AN XY: 74370

African (AFR) AF: 0.0113 AC: 471 AN: 41498

American (AMR) AF: 0.0371 AC: 566 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 122 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00707 AC: 34 AN: 4806

European-Finnish (FIN) AF: 0.0153 AC: 162 AN: 10596

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0519 AC: 3528 AN: 67980

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0458 Hom.: 596

Bravo AF: 0.0350

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0520

EpiControl AF: 0.0545

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	4	not provided (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	Papillary renal cell carcinoma type 1 (3)
-	-	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	-0.74
CADD	Benign	0.40
DANN	Benign	0.54
PhyloP100		-0.56
PromoterAI		0.0038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs11762213; hg19: chr7-116339282; COSMIC: COSV59257416;