rs376993881

Positions:

chr10-80275073-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000429.3(MAT1A):c.895C>T(p.Arg299Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000633 in 1,579,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

MAT1A
NM_000429.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.60

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 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000429.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr10-80275072-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 858071.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 10-80275073-G-A is Pathogenic according to our data. Variant chr10-80275073-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAT1A	NM_000429.3 linkuse as main transcript	c.895C>T	p.Arg299Cys	missense_variant	7/9	ENST00000372213.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
MAT1A	ENST00000372213.8 linkuse as main transcript	c.895C>T	p.Arg299Cys	missense_variant	7/9	1	NM_000429.3	P1
MAT1A	ENST00000480845.1 linkuse as main transcript	n.127C>T		non_coding_transcript_exon_variant	1/5	3
MAT1A	ENST00000485270.5 linkuse as main transcript	n.407C>T		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000256

AC:

AN:

195366

Hom.:

AF XY:

0.0000191

AC XY:

AN XY:

104866

show subpopulations

Gnomad AFR exome

AF:

0.0000898

Gnomad AMR exome

AF:

0.0000698

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000143

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000491

AC:

AN:

1427076

Hom.:

Cov.:

AF XY:

0.00000424

AC XY:

AN XY:

706748

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.0000508

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000106

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

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	Mar 18, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg299 amino acid residue in MAT1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20675163, 32496220). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects MAT1A function (PMID: 20675163). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 418870). This missense change has been observed in individuals with autosomal recessive hypermethioninemia (PMID: 20675163, 26933843). 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 sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 299 of the MAT1A protein (p.Arg299Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 09, 2023	The p.Arg299Cys variant in MAT1A has been reported in the homozygous state in 1 individual and in the compound heterozygote state in 4 individuals with hypermethioninemia and segregated with disease in 1 affected relative from 1 family (Fernandez-Irigoyen 2010 PMID: 20675163, Kim 2016 PMID: 26933843, Zhao 2022 PMID: 35760084). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 418870) and has also been identified in 0.007% (3/41418) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). In vitro functional studies provide some evidence that this variant significantly decreases methionine adenosyltransferase enzyme activity by ~80% compared to wildtype (Fernandez-Irigoyen 2010 PMID: 20675163) and computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hypermethioninemia due to methionine adenosyltransferase deficiency. ACMG/AMP Criteria applied: PM3, PS3_Supporting, PP3, PM2_Supporting, PP4. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2016

The R299C missense variant in the MAT1A gene has been reported previously inassociation with methionine adenosyltransferase I/III (MAT I/III) deficiency in a patient whowas homozygous for this variant (Fernandez-Irigoyen et al., 2010). Functional studiesfound that R299C results in low activities of both methionine adenosyltransferase andtripolyphosphatase (Fernandez-Irigoyen et al., 2010). The R219H variant has not been published as apathogenic variant, nor has it been reported as a benign variant to our knowledge. The R219H variantis a conservative amino acid substitution, which is not likely to impact secondary protein structure asthese residues share similar properties. This substitution occurs at a position that is conserved inmammals. In silico analysis is inconsistent in its predictions as to whether or not the variant isdamaging to the protein structure/function. Therefore, we interpret R299C as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.96

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.8

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MVP

0.96

MPC

1.9

ClinPred

1.0

GERP RS

5.0

Varity_R

0.96

gMVP

0.98

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