rs138556525

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_StrongPP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

MAT1A
NM_000429.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.55

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

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 id is 279845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAT1A	NM_000429.3 linkuse as main transcript	c.776C>T	p.Ala259Val	missense_variant	7/9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MAT1A	ENST00000372213.8 linkuse as main transcript	c.776C>T	p.Ala259Val	missense_variant	7/9	1	NM_000429.3	ENSP00000361287	P1
MAT1A	ENST00000480845.1 linkuse as main transcript	n.8C>T		non_coding_transcript_exon_variant	1/5	3
MAT1A	ENST00000485270.5 linkuse as main transcript	n.288C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247466

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134184

show subpopulations

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 SAS 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:

AN:

1459750

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000810

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000629

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	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; Invitae). ClinVar contains an entry for this variant (Variation ID: 279845). 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 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Apr 07, 2021	- -

MAT1A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2020

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 (Fernandez-Irigoyet et al., 2010); 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 (Fernandez-Irigoyet et al., 2010); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect; This variant is associated with the following publications: (PMID: 32335878, 20675163, 24445979, 23425511, 26933843, 28748147, 28492532, 31737040) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.8

REVEL

Pathogenic

0.89

Sift

Uncertain

0.022

Sift4G

Uncertain

0.023

Polyphen

0.97

Vest4

0.93

MVP

0.94

MPC

0.82

ClinPred

0.98

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.76

gMVP

0.94

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over