NM_000245.4:c.105G>C

Variant names:

• chr7-116699189-G-C
• rs376244358
• NM_000245.4:c.105G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_000245.4(MET):​c.105G>C​(p.Met35Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,848 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M35L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.04
• 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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17375907).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000526 (8/152156) while in subpopulation AFR AF = 0.000193 (8/41438). AF 95% confidence interval is 0.0000957. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.105G>C	p.Met35Ile	missense	Exon 2 of 21	NP_000236.2
	MET	NM_001127500.3		c.105G>C	p.Met35Ile	missense	Exon 2 of 21	NP_001120972.1
	MET	NM_001324401.3		c.105G>C	p.Met35Ile	missense	Exon 2 of 12	NP_001311330.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.105G>C	p.Met35Ile	missense	Exon 2 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.105G>C	p.Met35Ile	missense	Exon 2 of 21	ENSP00000317272.6
	MET	ENST00000456159.1	TSL:1	c.162G>C	p.Met54Ile	missense	Exon 3 of 3	ENSP00000413857.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249380 AF XY: 0.00

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727142

African (AFR) AF: 0.000239 AC: 8 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44692

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

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: 0.00000360 AC: 4 AN: 1111896

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

African (AFR) AF: 0.000193 AC: 8 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.00 AC: 0

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-predisposing syndrome (1)
-	-	1	Renal cell carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.12
Sift	Benign	0.048	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.84	P
Vest4		0.32
MutPred		0.33		Gain of sheet (P = 0.0266)
MVP		0.38
MPC		0.35
ClinPred		0.26	T
GERP RS		5.0
PromoterAI		-0.015	Neutral
Varity_R		0.26
gMVP		0.36
Mutation Taster		=89/11	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: rs376244358; hg19: chr7-116339243;