rs35775721

Variant names:

• chr7-116699618-C-T
• rs35775721
• NM_000245.4:c.534C>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.534C>T​(p.Ser178Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0482 in 1,613,868 control chromosomes in the GnomAD database, including 2,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (559 hom., cov: 32)
  • Exomes 𝑓: 0.046 (2121 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.145
• Publications: 30 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=-0.54).
• BP6: Variant 7-116699618-C-T is Benign according to our data. Variant chr7-116699618-C-T is described in ClinVar as Benign. ClinVar VariationId is 93578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.145 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.534C>T	p.Ser178Ser	synonymous	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.534C>T	p.Ser178Ser	synonymous	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.534C>T	p.Ser178Ser	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.534C>T	p.Ser178Ser	synonymous	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.534C>T	p.Ser178Ser	synonymous	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.534C>T		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10922 AN: 152076 Hom.: 556 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0432

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.0628

Gnomad SAS AF: 0.110

Gnomad FIN AF: 0.0533

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0411

Gnomad OTH AF: 0.0761

GnomAD2 exomes AF: 0.0566 AC: 13979 AN: 247062 AF XY: 0.0590

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0324

Gnomad EAS exome AF: 0.0666

Gnomad FIN exome AF: 0.0488

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0537

GnomAD4 exome AF: 0.0458 AC: 66881 AN: 1461674 Hom.: 2121 Cov.: 32 AF XY: 0.0479 AC XY: 34819 AN XY: 727134

African (AFR) AF: 0.143 AC: 4792 AN: 33464

American (AMR) AF: 0.0273 AC: 1222 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0344 AC: 899 AN: 26132

East Asian (EAS) AF: 0.0511 AC: 2029 AN: 39698

South Asian (SAS) AF: 0.113 AC: 9777 AN: 86258

European-Finnish (FIN) AF: 0.0498 AC: 2658 AN: 53348

Middle Eastern (MID) AF: 0.0926 AC: 534 AN: 5764

European-Non Finnish (NFE) AF: 0.0375 AC: 41688 AN: 1111924

Other (OTH) AF: 0.0544 AC: 3282 AN: 60382

GnomAD4 genome AF: 0.0719 AC: 10944 AN: 152194 Hom.: 559 Cov.: 32 AF XY: 0.0715 AC XY: 5322 AN XY: 74418

African (AFR) AF: 0.138 AC: 5727 AN: 41500

American (AMR) AF: 0.0433 AC: 662 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0329 AC: 114 AN: 3470

East Asian (EAS) AF: 0.0625 AC: 324 AN: 5180

South Asian (SAS) AF: 0.110 AC: 530 AN: 4820

European-Finnish (FIN) AF: 0.0533 AC: 565 AN: 10592

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0411 AC: 2794 AN: 68014

Other (OTH) AF: 0.0758 AC: 160 AN: 2112

Alfa AF: 0.0476 Hom.: 424

Bravo AF: 0.0724

Asia WGS AF: 0.0990 AC: 343 AN: 3478

EpiCase AF: 0.0416

EpiControl AF: 0.0429

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	Papillary renal cell carcinoma type 1 (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 97 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.4
DANN	Benign	0.68
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35775721; hg19: chr7-116339672; COSMIC: COSV59258982; COSMIC: COSV59258982;