NM_000429.3:c.790C>T

Variant names:

• chr10-80275178-G-A
• rs118204005
• NM_000429.3:c.790C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000429.3(MAT1A):​c.790C>T​(p.Arg264Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264H) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 1.84
• Publications: 12 publications found

Genes affected

MAT1A (HGNC:6903): (methionine adenosyltransferase 1A) This gene catalyzes a two-step reaction that involves the transfer of the adenosyl moiety of ATP to methionine to form S-adenosylmethionine and tripolyphosphate, which is subsequently cleaved to PPi and Pi. S-adenosylmethionine is the source of methyl groups for most biological methylations. The encoded protein is found as a homotetramer (MAT I) or a homodimer (MAT III) whereas a third form, MAT II (gamma), is encoded by the MAT2A gene. Mutations in this gene are associated with methionine adenosyltransferase deficiency. [provided by RefSeq, Jul 2008]

MAT1A Gene-Disease associations (from GenCC):

• methionine adenosyltransferase deficiency

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, G2P, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000429.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-80275177-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.654 (below the threshold of 3.09). Trascript score misZ: 2.3811 (below the threshold of 3.09). GenCC associations: The gene is linked to methionine adenosyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 10-80275178-G-A is Pathogenic according to our data. Variant chr10-80275178-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1210.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.790C>T	p.Arg264Cys	missense_variant	Exon 7 of 9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.790C>T	p.Arg264Cys	missense_variant	Exon 7 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000480845.1	n.22C>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
MAT1A	ENST00000485270.5	n.302C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461194 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 726850

African (AFR) AF: 0.0000299 AC: 1 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111782

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency Pathogenic:2

Feb 01, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 264 of the MAT1A protein (p.Arg264Cys). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MAT1A function (PMID: 10677294). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MAT1A protein function. ClinVar contains an entry for this variant (Variation ID: 1210). This missense change has been observed in individuals with autosomal recessive hypermethioninemia (PMID: 10677294, 15935930, 26289392). This variant is not present in population databases (gnomAD no frequency). -

MAT1A-related disorder Pathogenic:1

May 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The MAT1A c.790C>T variant is predicted to result in the amino acid substitution p.Arg264Cys. This variant has been reported to be causative for hypermethioninemia due to methionine adenosyltransferase I/III deficiency in the compound heterozygous state (referred to as c.791C>T (R264C) in Chamberlin et al. 2000. PubMed ID: 10677294; Chien et al. 2004. PubMed ID: 15935930; referred to as c.791C>T in Chien et al. 2015. PubMed ID: 26289392). In experimental studies, the p.Arg264Cys substitution abolished enzyme activity (Chamberlin et al. 2000. PubMed ID: 10677294). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		1.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Gain of methylation at K265 (P = 0.0363);
MVP		0.96
MPC		1.9
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.98
Mutation Taster		=13/87	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: rs118204005; hg19: chr10-82034934; COSMIC: COSV64746543; COSMIC: COSV64746543;