rs116528173

Variant names:

• chr10-80276432-C-T
• rs116528173
• NM_000429.3:c.712G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000429.3(MAT1A):​c.712G>A​(p.Glu238Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,614,150 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (2 hom.)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.946
• Publications: 5 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 20 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.654 (below the threshold of 3.09). Trascript score misZ: 2.3811 (below the threshold of 3.09). GenCC associations: The gene is linked to methionine adenosyltransferase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0056981146).
• BP6: Variant 10-80276432-C-T is Benign according to our data. Variant chr10-80276432-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 431707.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000328 (50/152334) while in subpopulation EAS AF = 0.00771 (40/5190). AF 95% confidence interval is 0.00582. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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.712G>A	p.Glu238Lys	missense	Exon 6 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.712G>A	p.Glu238Lys	missense	Exon 6 of 9	ENSP00000361287.3	Q00266
	MAT1A	ENST00000871627.1		c.712G>A	p.Glu238Lys	missense	Exon 6 of 9	ENSP00000541686.1
	MAT1A	ENST00000871624.1		c.877G>A	p.Glu293Lys	missense	Exon 6 of 9	ENSP00000541683.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00807

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000561 AC: 141 AN: 251354 AF XY: 0.000515

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000322 AC: 471 AN: 1461816 Hom.: 2 Cov.: 32 AF XY: 0.000348 AC XY: 253 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0104 AC: 413 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000234 AC: 26 AN: 1112010

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.000328 AC: 50 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000349 AC XY: 26 AN XY: 74484

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00771 AC: 40 AN: 5190

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000568 AC: 69

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	Hepatic methionine adenosyltransferase deficiency (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	8.8
DANN	Benign	0.97
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.70	N
PhyloP100		0.95
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.27
Sift	Benign	0.037	D
Sift4G	Benign	0.17	T
Polyphen		0.0060	B
Vest4		0.21
MVP		0.28
MPC		0.68
ClinPred		0.017	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.39
gMVP		0.57
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs116528173; hg19: chr10-82036188; COSMIC: COSV64747014; COSMIC: COSV64747014;