10-80275086-A-G

Position:

• chr10-80275086-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000429.3(MAT1A):​c.882T>C​(p.Ala294=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.675 in 1,589,642 control chromosomes in the GnomAD database, including 368,288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.74 (42444 hom., cov: 33)
  • Exomes 𝑓: 0.67 (325844 hom.)
• Consequence: MAT1A NM_000429.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -5.50

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BP6: Variant 10-80275086-A-G is Benign according to our data. Variant chr10-80275086-A-G is described in ClinVar as [Benign]. Clinvar id is 256107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-80275086-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.943 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAT1A	NM_000429.3	c.882T>C	p.Ala294=	synonymous_variant	7/9	ENST00000372213.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAT1A	ENST00000372213.8	c.882T>C	p.Ala294=	synonymous_variant	7/9	1	NM_000429.3	P1
MAT1A	ENST00000480845.1	n.114T>C		non_coding_transcript_exon_variant	1/5	3
MAT1A	ENST00000485270.5	n.394T>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes AF: 0.737 AC: 112004 AN: 151962 Hom.: 42406 Cov.: 33

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.554

Gnomad AMR AF: 0.755

Gnomad ASJ AF: 0.685

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.842

Gnomad FIN AF: 0.674

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.629

Gnomad OTH AF: 0.729

GnomAD3 exomes AF: 0.721 AC: 151977 AN: 210926 Hom.: 56159 AF XY: 0.716 AC XY: 81462 AN XY: 113698

Gnomad AFR exome AF: 0.890

Gnomad AMR exome AF: 0.793

Gnomad ASJ exome AF: 0.685

Gnomad EAS exome AF: 0.974

Gnomad SAS exome AF: 0.818

Gnomad FIN exome AF: 0.667

Gnomad NFE exome AF: 0.620

Gnomad OTH exome AF: 0.699

GnomAD4 exome AF: 0.668 AC: 960283 AN: 1437562 Hom.: 325844 Cov.: 55 AF XY: 0.670 AC XY: 477884 AN XY: 712864

Gnomad4 AFR exome AF: 0.900

Gnomad4 AMR exome AF: 0.791

Gnomad4 ASJ exome AF: 0.690

Gnomad4 EAS exome AF: 0.946

Gnomad4 SAS exome AF: 0.821

Gnomad4 FIN exome AF: 0.670

Gnomad4 NFE exome AF: 0.632

Gnomad4 OTH exome AF: 0.701

GnomAD4 genome AF: 0.737 AC: 112099 AN: 152080 Hom.: 42444 Cov.: 33 AF XY: 0.743 AC XY: 55233 AN XY: 74336

Gnomad4 AFR AF: 0.891

Gnomad4 AMR AF: 0.755

Gnomad4 ASJ AF: 0.685

Gnomad4 EAS AF: 0.966

Gnomad4 SAS AF: 0.842

Gnomad4 FIN AF: 0.674

Gnomad4 NFE AF: 0.629

Gnomad4 OTH AF: 0.732

Alfa AF: 0.655 Hom.: 42973

Bravo AF: 0.749

Asia WGS AF: 0.878 AC: 3054 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Hepatic methionine adenosyltransferase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.075
DANN	Benign	0.23

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

Other links and lift over

dbSNP: rs10887711; hg19: chr10-82034842;