rs376757912

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

10
5
4

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]

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: {Likely_pathogenic=1, Uncertain_significance=2, Pathogenic=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MAT1ANM_000429.3 linkc.529C>T p.Arg177Trp missense_variant Exon 5 of 9 ENST00000372213.8 NP_000420.1 Q00266

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MAT1AENST00000372213.8 linkc.529C>T p.Arg177Trp missense_variant Exon 5 of 9 1 NM_000429.3 ENSP00000361287.3 Q00266
MAT1AENST00000455001.1 linkc.340C>T p.Arg114Trp missense_variant Exon 4 of 5 5 ENSP00000414961.1 B1ANE6

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152130
Hom.:
0
Cov.:
32
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:
19
AN:
251364
Hom.:
0
AF XY:
0.000103
AC XY:
14
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:
40
AN:
1461834
Hom.:
0
Cov.:
30
AF XY:
0.0000371
AC XY:
27
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:
6
AN:
152248
Hom.:
0
Cov.:
32
AF XY:
0.0000403
AC XY:
3
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:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000988
AC:
12

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
Dec 11, 2024
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 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 autosomal recessive hypermethioninemia (PMID: 24445979, 26289392, 28186605, 31061746; internal data). 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). 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) has been performed 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. -

Aug 01, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: flagged submission
Collection Method: clinical testing

- -

MAT1A-related disorder Pathogenic:1
May 24, 2023
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Feb 28, 2025
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 26933843, 26289392, 24445979, 35760084, 31061746, 38380423, 28186605) -

not specified Uncertain:1
Jul 29, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
T
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.96
D;D
Eigen
Uncertain
0.25
Eigen_PC
Benign
0.021
FATHMM_MKL
Benign
0.51
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
4.3
H;.
PrimateAI
Benign
0.46
T
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
D
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.

Other links and lift over

dbSNP: rs376757912; hg19: chr10-82039949; COSMIC: COSV64746464; COSMIC: COSV64746464; API