7-116758554-C-G

Variant names:

• chr7-116758554-C-G
• rs201271860
• NM_000245.4:c.2198C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000245.4(MET):​c.2198C>G​(p.Thr733Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T733I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.33
• Publications: 2 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]

MET Gene-Disease associations (from GenCC):

• hereditary papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• papillary renal cell carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, ClinGen
• autosomal recessive nonsyndromic hearing loss 97

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteofibrous dysplasia

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• arthrogryposis, distal, IIa 11

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2280406).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.2198C>G	p.Thr733Arg	missense_variant	Exon 9 of 21	ENST00000397752.8	NP_000236.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.2198C>G	p.Thr733Arg	missense_variant	Exon 9 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.2198C>G	p.Thr733Arg	missense_variant	Exon 9 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.2198C>G		non_coding_transcript_exon_variant	Exon 9 of 20	1		ENSP00000410980.2
MET	ENST00000422097.2	c.2198C>G	p.Thr733Arg	missense_variant	Exon 9 of 12	3		ENSP00000398776.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249256 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.57	D;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.8	L;L;L;.
PhyloP100		2.3
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.086
Sift	Uncertain	0.0030	D;D;D;T
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.37	B;B;.;.
Vest4		0.26
MutPred		0.64		Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);Gain of solvent accessibility (P = 0.0808);.;
MVP		0.47
MPC		0.58
ClinPred		0.56	D
GERP RS		3.6
PromoterAI		0.011	Neutral
Varity_R		0.45
gMVP		0.84
Mutation Taster		=75/25	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: rs201271860; hg19: chr7-116398608;