rs755166920

Variant names:

• chr7-116700146-C-A
• rs755166920
• NM_000245.4:c.1062C>A

Your query was ambiguous. Multiple possible variants found:

• chr7-116700146-C-A
• chr7-116700146-C-G
• chr7-116700146-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000245.4(MET):​c.1062C>A​(p.Ala354Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000554 in 1,444,652 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A354A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.93
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 7-116700146-C-A is Benign according to our data. Variant chr7-116700146-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2042430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.93 with no splicing effect.

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.1062C>A	p.Ala354Ala	synonymous	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.1062C>A	p.Ala354Ala	synonymous	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.1062C>A	p.Ala354Ala	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.1062C>A	p.Ala354Ala	synonymous	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1062C>A	p.Ala354Ala	synonymous	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1062C>A		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000554 AC: 8 AN: 1444652 Hom.: 0 Cov.: 32 AF XY: 0.00000698 AC XY: 5 AN XY: 716760

African (AFR) AF: 0.00 AC: 0 AN: 32698

American (AMR) AF: 0.00 AC: 0 AN: 42434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 82746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1104172

Other (OTH) AF: 0.00 AC: 0 AN: 59558

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	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	-0.65
CADD	Benign	0.031
DANN	Benign	0.63
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs755166920; hg19: chr7-116340200;