10-80280745-A-T

Variant names:

• chr10-80280745-A-T
• rs761462996
• NM_000429.3:c.340T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000429.3(MAT1A):​c.340T>A​(p.Ser114Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S114F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.73
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.340T>A	p.Ser114Thr	missense_variant	Exon 4 of 9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.340T>A	p.Ser114Thr	missense_variant	Exon 4 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000455001.1	c.151T>A	p.Ser51Thr	missense_variant	Exon 3 of 5	5		ENSP00000414961.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.5	H;.
PhyloP100		4.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	N;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.57	P;.
Vest4		0.70
MutPred		0.74		Loss of disorder (P = 0.2034);.;
MVP		0.61
MPC		0.99
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.85
gMVP		0.95
Mutation Taster		=22/78	disease causing

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: rs761462996; hg19: chr10-82040501;