rs376757912

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_000429.3(MAT1A):c.529C>T(p.Arg177Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,082 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

MAT1A
NM_000429.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:2

Conservation

PhyloP100: 0.519

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 Uncertain_significance. Variant got 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.88

PP5

Variant 10-80280193-G-A is Pathogenic according to our data. Variant chr10-80280193-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 426944.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAT1A	NM_000429.3 linkuse as main transcript	c.529C>T	p.Arg177Trp	missense_variant	5/9	ENST00000372213.8	NP_000420.1	Q00266

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8 linkuse as main transcript	c.529C>T	p.Arg177Trp	missense_variant	5/9	1	NM_000429.3	ENSP00000361287.3		Q00266
MAT1A	ENST00000455001.1 linkuse as main transcript	c.340C>T	p.Arg114Trp	missense_variant	4/5	5		ENSP00000414961.1		B1ANE6

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251364

Hom.:

AF XY:

0.000103

AC XY:

AN XY:

135886

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461834

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000567

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Revvity Omics, Revvity	Aug 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 177 of the MAT1A protein (p.Arg177Trp). This variant is present in population databases (rs376757912, gnomAD 0.04%). This missense change has been observed in individual(s) with hypermethioninemia (PMID: 24445979, 26289392, 28186605, 31061746; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 426944). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MAT1A protein function. For these reasons, this variant has been classified as Pathogenic. -

MAT1A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2023

The MAT1A c.529C>T variant is predicted to result in the amino acid substitution p.Arg177Trp. This variant has been reported in the homozygous or compound heterozygous state in individuals with hypermethioninemia (Chien et al 2015. PubMed ID: 26289392; Sun et al 2017. PubMed ID: 28186605; Zhao et al. 2022. PubMed ID: 35760084). It has also been reported in patients with abnormal newborn screen results (Chadwick et al 2014. PubMed ID: 24445979; Sen et al. 2019. PubMed ID: 31061746; Zhang et al. 2020. PubMed ID: 31851615). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-82039949-G-A). This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26933843, 26289392, 24445979, 28186605, 35760084, 31061746) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 29, 2024

Variant summary: MAT1A c.529C>T (p.Arg177Trp) results in a non-conservative amino acid change located in the S-adenosylmethionine synthetase, central domain (IPR022629) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251364 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MAT1A causing Hepatic methionine adenosyltransferase deficiency, allowing no conclusion about variant significance. c.529C>T has been reported in the literature as homozygous, compount heterozygous, or heterozygous genotype in individuals affected with hypermethioninemia without evidence of CNS abnormalities (Chadwick_2014, Chien_2015, Sen_2019, Sun_2017, Zhao_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hepatic methionine adenosyltransferase deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24445979, 26289392, 31061746, 28186605, 35760084). ClinVar contains an entry for this variant (Variation ID: 426944). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Uncertain

0.061

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.021

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.95

D;D

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

4.3

H;.

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

0.60

MPC

1.6

ClinPred

0.98

GERP RS

-0.48

Varity_R

0.87

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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