rs2993763

Variant names:

• chr10-80273838-G-A
• rs2993763
• NM_000429.3:c.1131C>T
• MAT1A p.Tyr377Tyr

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.1131C>T​(p.Tyr377Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,610,836 control chromosomes in the GnomAD database, including 187,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (23794 hom., cov: 32)
  • Exomes 𝑓: 0.47 (163800 hom.)
• Consequence: MAT1A NM_000429.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.471
• Publications: 34 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 10-80273838-G-A is Benign according to our data. Variant chr10-80273838-G-A is described in ClinVar as Benign. ClinVar VariationId is 256104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.471 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000429.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAT1A	NM_000429.3	MANE Select	c.1131C>T	p.Tyr377Tyr	synonymous	Exon 9 of 9	NP_000420.1	Q00266

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAT1A	ENST00000372213.8	TSL:1 MANE Select	c.1131C>T	p.Tyr377Tyr	synonymous	Exon 9 of 9	ENSP00000361287.3	Q00266
	MAT1A	ENST00000871627.1		c.1347C>T	p.Tyr449Tyr	synonymous	Exon 9 of 9	ENSP00000541686.1
	MAT1A	ENST00000871624.1		c.1296C>T	p.Tyr432Tyr	synonymous	Exon 9 of 9	ENSP00000541683.1

Frequencies

GnomAD3 genomes AF: 0.543 AC: 82513 AN: 151940 Hom.: 23755 Cov.: 32

Gnomad AFR AF: 0.747

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.543

Gnomad ASJ AF: 0.470

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.645

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.444

Gnomad OTH AF: 0.517

GnomAD2 exomes AF: 0.506 AC: 126549 AN: 250074 AF XY: 0.505

Gnomad AFR exome AF: 0.752

Gnomad AMR exome AF: 0.544

Gnomad ASJ exome AF: 0.479

Gnomad EAS exome AF: 0.455

Gnomad FIN exome AF: 0.429

Gnomad NFE exome AF: 0.453

Gnomad OTH exome AF: 0.496

GnomAD4 exome AF: 0.468 AC: 682324 AN: 1458778 Hom.: 163800 Cov.: 38 AF XY: 0.471 AC XY: 341894 AN XY: 725856

African (AFR) AF: 0.759 AC: 25345 AN: 33414

American (AMR) AF: 0.548 AC: 24501 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 12435 AN: 26112

East Asian (EAS) AF: 0.408 AC: 16177 AN: 39682

South Asian (SAS) AF: 0.626 AC: 53922 AN: 86198

European-Finnish (FIN) AF: 0.429 AC: 22913 AN: 53416

Middle Eastern (MID) AF: 0.554 AC: 3184 AN: 5744

European-Non Finnish (NFE) AF: 0.446 AC: 494377 AN: 1109250

Other (OTH) AF: 0.489 AC: 29470 AN: 60250

GnomAD4 genome AF: 0.543 AC: 82615 AN: 152058 Hom.: 23794 Cov.: 32 AF XY: 0.545 AC XY: 40539 AN XY: 74332

African (AFR) AF: 0.747 AC: 30995 AN: 41510

American (AMR) AF: 0.543 AC: 8301 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.470 AC: 1632 AN: 3472

East Asian (EAS) AF: 0.454 AC: 2335 AN: 5146

South Asian (SAS) AF: 0.646 AC: 3113 AN: 4816

European-Finnish (FIN) AF: 0.424 AC: 4486 AN: 10570

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.444 AC: 30195 AN: 67940

Other (OTH) AF: 0.519 AC: 1098 AN: 2114

Alfa AF: 0.481 Hom.: 63527

Bravo AF: 0.556

Asia WGS AF: 0.573 AC: 1995 AN: 3478

EpiCase AF: 0.455

EpiControl AF: 0.447

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Hepatic methionine adenosyltransferase deficiency (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.26
DANN	Benign	0.33
PhyloP100		-0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2993763;

hg19: chr10-82033594;

COSMIC: COSV64745496;

COSMIC: COSV64745496;