rs118204004

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000429.3(MAT1A):c.914T>C(p.Leu305Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,413,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

MAT1A
NM_000429.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.95

Publications

8 publications found

Variant links:

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

MAT1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a helix (size 17) in uniprot entity METK1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000429.3

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, 0.992

PP5

Variant 10-80275054-A-G is Pathogenic according to our data. Variant chr10-80275054-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1205.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3 link	c.914T>C	p.Leu305Pro	missense_variant	Exon 7 of 9	ENST00000372213.8	NP_000420.1	Q00266

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAT1A	ENST00000372213.8 link	c.914T>C	p.Leu305Pro	missense_variant	Exon 7 of 9	1	NM_000429.3	ENSP00000361287.3	Q00266
MAT1A	ENST00000480845.1 link	n.146T>C		non_coding_transcript_exon_variant	Exon 1 of 5	3
MAT1A	ENST00000485270.5 link	n.426T>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.08e-7

AC:

AN:

1413010

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

698502

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32140

American (AMR)

AF:

0.00

AC:

AN:

37376

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25304

East Asian (EAS)

AF:

0.00

AC:

AN:

36708

South Asian (SAS)

AF:

0.00

AC:

AN:

80388

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4858

European-Non Finnish (NFE)

AF:

9.19e-7

AC:

AN:

1087576

Other (OTH)

AF:

0.00

AC:

AN:

58496

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency

Pathogenic:1

Oct 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

PhyloP100

8.9

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.3

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

1.0

MutPred

0.93

Gain of catalytic residue at L305 (P = 0.0047);

MVP

0.97

MPC

2.0

ClinPred

1.0

GERP RS

5.0

Varity_R

0.99

gMVP

0.98

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over