rs121913247

Positions:

• chr7-116783359-T-A
• chr7-116783359-T-C
• chr7-116783359-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000245.4(MET):​c.3688T>A​(p.Tyr1230Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. Y1230D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a turn (size 3) in uniprot entity MET_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MET	NM_000245.4	c.3688T>A	p.Tyr1230Asn	missense_variant	19/21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3742T>A	p.Tyr1248Asn	missense_variant	19/21		NP_001120972.1
MET	NM_001324402.2	c.2398T>A	p.Tyr800Asn	missense_variant	18/20		NP_001311331.1
MET	XM_011516223.2	c.3745T>A	p.Tyr1249Asn	missense_variant	20/22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3688T>A	p.Tyr1230Asn	missense_variant	19/21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3742T>A	p.Tyr1248Asn	missense_variant	19/21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1293T>A		non_coding_transcript_exon_variant	18/20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1293T>A		3_prime_UTR_variant	18/20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.85	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	1.5	L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.82
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.66		Gain of disorder (P = 0.0374);.;
MVP		0.93
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.93

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-116423413;