rs138556525

Variant names:

• chr10-80275192-G-A
• rs138556525
• NM_000429.3:c.776C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-80275192-G-A
• chr10-80275192-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PP2 PP3_Strong PP5_Very_Strong

The NM_000429.3(MAT1A):​c.776C>T​(p.Ala259Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,459,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A259A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.55
• Publications: 15 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 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000429.3
• 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, 0.954
• PP5: Variant 10-80275192-G-A is Pathogenic according to our data. Variant chr10-80275192-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 279845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.776C>T	p.Ala259Val	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.776C>T	p.Ala259Val	missense_variant	Exon 7 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000480845.1	n.8C>T		non_coding_transcript_exon_variant	Exon 1 of 5	3
MAT1A	ENST00000485270.5	n.288C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000121 AC: 3 AN: 247466 AF XY: 0.0000149

Gnomad AFR exome AF: 0.0000644

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1459750 Hom.: 0 Cov.: 33 AF XY: 0.00000689 AC XY: 5 AN XY: 726106

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000810 AC: 9 AN: 1111134

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000210 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency Pathogenic:3

Apr 07, 2021

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 259 of the MAT1A protein (p.Ala259Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal dominant hypermethioninemia (PMID: 20675163, 24445979, 28748147; internal data). ClinVar contains an entry for this variant (Variation ID: 279845). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAT1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAT1A function (PMID: 23425511, 26933843, 28748147). For these reasons, this variant has been classified as Pathogenic. -

MAT1A-related disorder Pathogenic:1

Sep 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MAT1A c.776C>T variant is predicted to result in the amino acid substitution p.Ala259Val. This variant has previously been reported in two presumably unrelated patients with hypermethioninemia (Fernández-Irigoyen et al. 2010. PubMed ID: 20675163; Chadwick et al. 2014. PubMed ID: 24445979). The patient reported by Fernández-Irigoyen had greatly decreased methionine adenosyltransferase I/III activity. Additionally, a parent-child pair was reported with both individuals carrying this variant in the heterozygous state. In this family, the mother was also found to exhibit hypermethioninemia. As a result, the authors suggested that this variant may cause autosomal dominant hypermethioninemia (Muriello et al. 2017. PubMed ID: 28748147). In a recent study, four additional patients with hypermethioninemia were reported to harbor this variant in the heterozygous state alone, consistent with autosomal dominant inheritance (Tong et al. 2022. PubMed ID: 36704196). The p.Ala259Val amino acid is predicted to affect protein dimerization, similarly to the commonly reported autosomal dominant p.Arg264His change and other residues localized to the dimer interface (Shafqat et al. 2013. PubMed ID: 23425511; Kim et al. 2016. PubMed ID: 26933843; Muriello et al. 2017. PubMed ID: 28748147). In an expression study in E. coli cells, the p.Ala259Val substitution decreased the methionine adenosyltransferase enzyme activity to less than 20% of control (Fernández-Irigoyen et al. 2010. PubMed ID: 20675163). This variant is reported in 0.0064% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-82034948-G-A). Taken together, we classify this variant as pathogenic. -

not provided Pathogenic:1

Mar 02, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Expression studies found that A259V was associated with an approximately 80-95% reduction in methionine adenosyltransferase (MATI/III) activity compared with wild-type enzyme while tripolyphosphatase activity, the second step in the reaction catalyzed by MAT I/III enzyme, was only slightly reduced (PMID: 20675163); Majority of MAT1A pathogenic variants are inherited in an autosomal recessive manner; however, dominant inheritance has been well documented for a single R264H missense variant. At this time, there is not enough evidence to support A259V as a dominant variant (PMID: 20675163); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32335878, 24445979, 23425511, 26933843, 28748147, 28492532, 38582244, 20675163, 36704196, 31737040, 32778825, 33726816) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.023	D
Polyphen		0.97	D
Vest4		0.93
MVP		0.94
MPC		0.82
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.94
Mutation Taster		=10/90	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: rs138556525; hg19: chr10-82034948; COSMIC: COSV64745256; COSMIC: COSV64745256;