rs1554400071

Variant names:

• chr7-116781989-A-C
• rs1554400071
• NM_000245.4:c.3524A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-116781989-A-C
• chr7-116781989-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000245.4(MET):​c.3524A>C​(p.Asn1175Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1175S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MET NM_000245.4 missense, splice_region
• Scores: Splicing: ADA: 0.0002582
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.29
• 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]

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 27 uncertain in NM_000245.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23703215).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MET	NM_000245.4	c.3524A>C	p.Asn1175Thr	missense_variant, splice_region_variant	Exon 18 of 21	ENST00000397752.8	NP_000236.2
MET	NM_001127500.3	c.3578A>C	p.Asn1193Thr	missense_variant, splice_region_variant	Exon 18 of 21		NP_001120972.1
MET	NM_001324402.2	c.2234A>C	p.Asn745Thr	missense_variant, splice_region_variant	Exon 17 of 20		NP_001311331.1
MET	XM_011516223.2	c.3581A>C	p.Asn1194Thr	missense_variant, splice_region_variant	Exon 19 of 22		XP_011514525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MET	ENST00000397752.8	c.3524A>C	p.Asn1175Thr	missense_variant, splice_region_variant	Exon 18 of 21	1	NM_000245.4	ENSP00000380860.3
MET	ENST00000318493.11	c.3578A>C	p.Asn1193Thr	missense_variant, splice_region_variant	Exon 18 of 21	1		ENSP00000317272.6
MET	ENST00000436117.3	n.*1129A>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 17 of 20	1		ENSP00000410980.2
MET	ENST00000436117.3	n.*1129A>C		3_prime_UTR_variant	Exon 17 of 20	1		ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Renal cell carcinoma Uncertain:1

Dec 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 454243). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1193 of the MET protein (p.Asn1193Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Uncertain	0.78	D;.
Eigen	Benign	-0.032
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.73	N;.
PhyloP100		5.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.56	P;B
Vest4		0.41
MutPred		0.40		Gain of phosphorylation at N1175 (P = 0.0909);.;
MVP		0.78
MPC		1.1
ClinPred		0.90	D
GERP RS		2.2
Varity_R		0.77
gMVP		0.67
Mutation Taster		=25/75	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.022
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: rs1554400071; hg19: chr7-116422043;