chr7-116699172-C-G

Variant names:

• chr7-116699172-C-G
• rs1060504939
• NM_000245.4:c.88C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001127500.3(MET):​c.88C>G​(p.Leu30Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L30P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MET NM_001127500.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.43
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04651043).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127500.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.88C>G	p.Leu30Val	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.88C>G	p.Leu30Val	missense	Exon 2 of 21	NP_001120972.1
	MET	NM_001324401.3		c.88C>G	p.Leu30Val	missense	Exon 2 of 12	NP_001311330.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.88C>G	p.Leu30Val	missense	Exon 2 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.88C>G	p.Leu30Val	missense	Exon 2 of 21	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.145C>G	p.Leu49Val	missense	Exon 3 of 3	ENSP00000413857.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727134

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111888

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.20
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.24	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.4
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.086
Sift	Benign	0.75	T
Sift4G	Benign	0.24	T
Polyphen		0.13	B
Vest4		0.12
MutPred		0.30		Loss of stability (P = 0.1049)
MVP		0.25
MPC		0.89
ClinPred		0.036	T
GERP RS		3.3
PromoterAI		0.0036	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.091
gMVP		0.25
Mutation Taster		=87/13	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: rs1060504939; hg19: chr7-116339226;