NM_000245.4:c.3280C>T

Variant names:

• chr7-116777409-C-T
• rs121913244
• NM_000245.4:c.3280C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000245.4(MET):​c.3280C>T​(p.His1094Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. H1094P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MET NM_000245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 22 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 22 uncertain 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 chr7-116777410-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.926

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	NM_000245.4	MANE Select	c.3280C>T	p.His1094Tyr	missense	Exon 16 of 21	NP_000236.2
	MET	NM_001127500.3		c.3334C>T	p.His1112Tyr	missense	Exon 16 of 21	NP_001120972.1
	MET	NM_001324402.2		c.1990C>T	p.His664Tyr	missense	Exon 15 of 20	NP_001311331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MET	ENST00000397752.8	TSL:1 MANE Select	c.3280C>T	p.His1094Tyr	missense	Exon 16 of 21	ENSP00000380860.3
	MET	ENST00000318493.11	TSL:1	c.3334C>T	p.His1112Tyr	missense	Exon 16 of 21	ENSP00000317272.6
	MET	ENST00000436117.3	TSL:1	n.*885C>T		non_coding_transcript_exon	Exon 15 of 20	ENSP00000410980.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Sep 02, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1112Y variant (also known as c.3334C>T), located in coding exon 15 of the MET gene, results from a C to T substitution at nucleotide position 3334. The histidine at codon 1112 is replaced by tyrosine, an amino acid with similar properties. This variant was reported in individual(s) with features consistent with MET-related papillary renal cell carcinoma (Schmidt L et al. Oncogene, 1999 Apr;18:2343-50). In an assay testing MET function, this variant showed a functionally abnormal result (Sebai M et al. Hum Mutat, 2022 Mar;43:316-327). Other variant(s) at the same codon, p.H1112R (c.3335A>G), have been identified in individual(s) with features consistent with MET-related papillary renal cell carcinoma (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.83		Loss of catalytic residue at G1095 (P = 0.0895)
MVP		0.79
MPC		0.96
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.95
gMVP		0.75
Mutation Taster		=172/128	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs121913244; hg19: chr7-116417463; COSMIC: COSV59256829; COSMIC: COSV59256829;