7-116700215-C-T

Variant names:

• chr7-116700215-C-T
• rs28444388
• NM_000245.4:c.1131C>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.1131C>T​(p.Ile377Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0112 in 1,594,374 control chromosomes in the GnomAD database, including 1,605 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I377I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.057 (846 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (759 hom.)
• Consequence: MET NM_000245.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.288
• Publications: 11 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=-0.51).
• BP6: Variant 7-116700215-C-T is Benign according to our data. Variant chr7-116700215-C-T is described in ClinVar as Benign. ClinVar VariationId is 93566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.288 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.196 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.1131C>T	p.Ile377Ile	synonymous	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.1131C>T	p.Ile377Ile	synonymous	Exon 2 of 21	NP_001120972.1	P08581-2
	MET	NM_001324401.3		c.1131C>T	p.Ile377Ile	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.1131C>T	p.Ile377Ile	synonymous	Exon 2 of 21	ENSP00000380860.3	P08581-1
	MET	ENST00000318493.11	TSL:1	c.1131C>T	p.Ile377Ile	synonymous	Exon 2 of 21	ENSP00000317272.6	P08581-2
	MET	ENST00000436117.3	TSL:1	n.1131C>T		non_coding_transcript_exon	Exon 2 of 20	ENSP00000410980.2	P08581-3

Frequencies

GnomAD3 genomes AF: 0.0573 AC: 8714 AN: 152074 Hom.: 844 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0157 AC: 3588 AN: 228660 AF XY: 0.0119

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.00765

Gnomad ASJ exome AF: 0.00849

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000484

Gnomad NFE exome AF: 0.000963

Gnomad OTH exome AF: 0.00719

GnomAD4 exome AF: 0.00628 AC: 9050 AN: 1442184 Hom.: 759 Cov.: 32 AF XY: 0.00545 AC XY: 3909 AN XY: 716616

African (AFR) AF: 0.209 AC: 6722 AN: 32236

American (AMR) AF: 0.00895 AC: 356 AN: 39768

Ashkenazi Jewish (ASJ) AF: 0.00935 AC: 233 AN: 24930

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39628

South Asian (SAS) AF: 0.000920 AC: 75 AN: 81514

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52812

Middle Eastern (MID) AF: 0.0314 AC: 177 AN: 5642

European-Non Finnish (NFE) AF: 0.000586 AC: 648 AN: 1106128

Other (OTH) AF: 0.0140 AC: 835 AN: 59526

GnomAD4 genome AF: 0.0574 AC: 8729 AN: 152190 Hom.: 846 Cov.: 32 AF XY: 0.0557 AC XY: 4146 AN XY: 74398

African (AFR) AF: 0.199 AC: 8262 AN: 41486

American (AMR) AF: 0.0167 AC: 256 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.000912 AC: 62 AN: 68008

Other (OTH) AF: 0.0408 AC: 86 AN: 2110

Alfa AF: 0.0234 Hom.: 280

Bravo AF: 0.0649

Asia WGS AF: 0.0100 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	4	Papillary renal cell carcinoma type 1 (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.49
DANN	Benign	0.82
PhyloP100		-0.29
Mutation Taster		=93/7	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: rs28444388; hg19: chr7-116340269; COSMIC: COSV59258618;