7-116778953-C-T

Variant names:

• chr7-116778953-C-T
• rs121913675
• NM_000245.4:c.3518C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_000245.4(MET):​c.3518C>T​(p.Thr1173Ile) 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. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1173A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.14
• Publications: 4 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-116778953-C-T is Pathogenic according to our data. Variant chr7-116778953-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 13888.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37027508). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3518C>T	p.Thr1173Ile	missense_variant	Exon 17 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3572C>T	p.Thr1191Ile	missense_variant	Exon 17 of 21		NP_001120972.1
MET	NM_001324402.2	c.2228C>T	p.Thr743Ile	missense_variant	Exon 16 of 20		NP_001311331.1
MET	XM_011516223.2	c.3575C>T	p.Thr1192Ile	missense_variant	Exon 18 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3518C>T	p.Thr1173Ile	missense_variant	Exon 17 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3572C>T	p.Thr1191Ile	missense_variant	Exon 17 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1123C>T		non_coding_transcript_exon_variant	Exon 16 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1123C>T		3_prime_UTR_variant	Exon 16 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Pediatric hepatocellular carcinoma Pathogenic:1

Jan 15, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.37	T;T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.1	L;.
PhyloP100		2.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.97	D;P
Vest4		0.60
MutPred		0.47		Loss of phosphorylation at T1173 (P = 0.0504);.;
MVP		0.53
MPC		1.9
ClinPred		0.72	D
GERP RS		5.5
Varity_R		0.56
gMVP		0.61
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs121913675; hg19: chr7-116419007; COSMIC: COSV59272241;