10-80280296-A-G

Variant names:

• chr10-80280296-A-G
• rs1143694
• NM_000429.3:c.426T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000429.3(MAT1A):​c.426T>C​(p.Ala142Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,613,670 control chromosomes in the GnomAD database, including 409,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.77 (46318 hom., cov: 30)
  • Exomes 𝑓: 0.70 (362787 hom.)
• Consequence: MAT1A NM_000429.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.585
• Publications: 24 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 10-80280296-A-G is Benign according to our data. Variant chr10-80280296-A-G is described in ClinVar as Benign. ClinVar VariationId is 256105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.585 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.945 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.426T>C	p.Ala142Ala	synonymous_variant	Exon 5 of 9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.426T>C	p.Ala142Ala	synonymous_variant	Exon 5 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000455001.1	c.237T>C	p.Ala79Ala	synonymous_variant	Exon 4 of 5	5		ENSP00000414961.1

Frequencies

GnomAD3 genomes AF: 0.770 AC: 116921 AN: 151772 Hom.: 46259 Cov.: 30

Gnomad AFR AF: 0.936

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.748

Gnomad EAS AF: 0.968

Gnomad SAS AF: 0.853

Gnomad FIN AF: 0.697

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.661

Gnomad OTH AF: 0.764

GnomAD2 exomes AF: 0.756 AC: 190035 AN: 251342 AF XY: 0.751

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.816

Gnomad ASJ exome AF: 0.756

Gnomad EAS exome AF: 0.975

Gnomad FIN exome AF: 0.699

Gnomad NFE exome AF: 0.667

Gnomad OTH exome AF: 0.734

GnomAD4 exome AF: 0.700 AC: 1022897 AN: 1461780 Hom.: 362787 Cov.: 63 AF XY: 0.702 AC XY: 510239 AN XY: 727178

African (AFR) AF: 0.944 AC: 31593 AN: 33480

American (AMR) AF: 0.814 AC: 36383 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.755 AC: 19736 AN: 26136

East Asian (EAS) AF: 0.948 AC: 37631 AN: 39700

South Asian (SAS) AF: 0.835 AC: 72051 AN: 86256

European-Finnish (FIN) AF: 0.697 AC: 37215 AN: 53372

Middle Eastern (MID) AF: 0.820 AC: 4731 AN: 5766

European-Non Finnish (NFE) AF: 0.665 AC: 739203 AN: 1111956

Other (OTH) AF: 0.734 AC: 44354 AN: 60390

GnomAD4 genome AF: 0.771 AC: 117040 AN: 151890 Hom.: 46318 Cov.: 30 AF XY: 0.775 AC XY: 57513 AN XY: 74196

African (AFR) AF: 0.936 AC: 38794 AN: 41446

American (AMR) AF: 0.782 AC: 11952 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.748 AC: 2598 AN: 3472

East Asian (EAS) AF: 0.967 AC: 4967 AN: 5134

South Asian (SAS) AF: 0.852 AC: 4080 AN: 4786

European-Finnish (FIN) AF: 0.697 AC: 7340 AN: 10538

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.661 AC: 44909 AN: 67926

Other (OTH) AF: 0.766 AC: 1614 AN: 2106

Alfa AF: 0.711 Hom.: 77576

Bravo AF: 0.784

Asia WGS AF: 0.891 AC: 3096 AN: 3478

EpiCase AF: 0.673

EpiControl AF: 0.670

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hepatic methionine adenosyltransferase deficiency Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.5
DANN	Benign	0.49
PhyloP100		0.58
Mutation Taster		=98/2	polymorphism (auto)

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: rs1143694; hg19: chr10-82040052; COSMIC: COSV64746096; COSMIC: COSV64746096;