7-116699124-C-T

Variant names:

• chr7-116699124-C-T
• rs763344951
• NM_000245.4:c.40C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001127500.3(MET):​c.40C>T​(p.Leu14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MET NM_001127500.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 0.561
• 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.090137035).
• BP6: Variant 7-116699124-C-T is Benign according to our data. Variant chr7-116699124-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 188112.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000145 (22/152118) while in subpopulation AMR AF = 0.000917 (14/15270). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.40C>T	p.Leu14Phe	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.40C>T	p.Leu14Phe	missense	Exon 2 of 21	NP_001120972.1
	MET	NM_001324401.3		c.40C>T	p.Leu14Phe	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.40C>T	p.Leu14Phe	missense	Exon 2 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.40C>T	p.Leu14Phe	missense	Exon 2 of 21	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.97C>T	p.Leu33Phe	missense	Exon 3 of 3	ENSP00000413857.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000882 AC: 22 AN: 249328 AF XY: 0.000104

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000972

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000109 AC: 159 AN: 1461642 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000179 AC: 8 AN: 44692

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

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

European-Non Finnish (NFE) AF: 0.000131 AC: 146 AN: 1111852

Other (OTH) AF: 0.0000828 AC: 5 AN: 60380

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.000917 AC: 14 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000966 Hom.: 0

Bravo AF: 0.000181

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Autosomal recessive nonsyndromic hearing loss 97 (1)
-	-	1	Hereditary cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	MET-related disorder (1)
-	-	1	Papillary renal cell carcinoma type 1 (1)
-	1	-	Papillary renal cell carcinoma type 1;C2239176:Hepatocellular carcinoma (1)
-	1	-	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.094
Eigen_PC	Benign	0.084
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.56
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.065
Sift	Benign	0.15	T
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.093
MVP		0.42
MPC		0.28
ClinPred		0.026	T
GERP RS		4.1
PromoterAI		0.037	Neutral
Varity_R		0.072
gMVP		0.50
Mutation Taster		=79/21	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs763344951; hg19: chr7-116339178;