rs2994388

chr10-80274506-G-Achr10-80274506-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000429.3(MAT1A):c.1085+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,602 control chromosomes in the GnomAD database, including 187,721 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23804 hom., cov: 32)
  • Exomes 𝑓: 0.47 (163917 hom.)
• Consequence: MAT1A NM_000429.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.117

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-80274506-G-A is Benign according to our data. Variant chr10-80274506-G-A is described in ClinVar as [Benign]. Clinvar id is 256103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-80274506-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAT1A	NM_000429.3	c.1085+14C>T		intron_variant		ENST00000372213.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAT1A	ENST00000372213.8	c.1085+14C>T		intron_variant		1	NM_000429.3	P1
MAT1A	ENST00000480845.1	n.317+14C>T		intron_variant, non_coding_transcript_variant		3
MAT1A	ENST00000485270.5	n.597+14C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82509 AN: 151952 Hom.: 23765 Cov.: 32

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.345

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.516

GnomAD3 exomes AF: 0.506 AC: 127090 AN: 251288 Hom.: 33272 AF XY: 0.505 AC XY: 68547 AN XY: 135858

Gnomad AFR exome AF: 0.753

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.455

Gnomad SAS exome AF: 0.624

Gnomad FIN exome AF: 0.430

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.468 AC: 683826 AN: 1461532 Hom.: 163917 Cov.: 49 AF XY: 0.471 AC XY: 342566 AN XY: 727082

Gnomad4 AFR exome AF: 0.759

Gnomad4 AMR exome AF: 0.548

Gnomad4 ASJ exome AF: 0.476

Gnomad4 EAS exome AF: 0.408

Gnomad4 SAS exome AF: 0.625

Gnomad4 FIN exome AF: 0.429

Gnomad4 NFE exome AF: 0.446

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.543 AC: 82611 AN: 152070 Hom.: 23804 Cov.: 32 AF XY: 0.546 AC XY: 40551 AN XY: 74336

Gnomad4 AFR AF: 0.747

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.470

Gnomad4 EAS AF: 0.453

Gnomad4 SAS AF: 0.646

Gnomad4 FIN AF: 0.424

Gnomad4 NFE AF: 0.444

Gnomad4 OTH AF: 0.519

Alfa AF: 0.465 Hom.: 29888

Bravo AF: 0.556

Asia WGS AF: 0.573 AC: 1995 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.13
Dann	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2994388; hg19: chr10-82034262; COSMIC: COSV64745501; COSMIC: COSV64745501;