rs886039820

Variant names:

• chr2-85542980-A-C
• rs886039820
• NM_005911.6:c.1031A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_005911.6(MAT2A):​c.1031A>C​(p.Glu344Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MAT2A NM_005911.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.87

Genes affected

MAT2A (HGNC:6904): (methionine adenosyltransferase 2A) The protein encoded by this gene catalyzes the production of S-adenosylmethionine (AdoMet) from methionine and ATP. AdoMet is the key methyl donor in cellular processes. [provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873
• PP5: Variant 2-85542980-A-C is Pathogenic according to our data. Variant chr2-85542980-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 265866.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-85542980-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT2A	NM_005911.6	c.1031A>C	p.Glu344Ala	missense_variant	Exon 8 of 9	ENST00000306434.8	NP_005902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT2A	ENST00000306434.8	c.1031A>C	p.Glu344Ala	missense_variant	Exon 8 of 9	1	NM_005911.6	ENSP00000303147.3
MAT2A	ENST00000409017.1	c.842A>C	p.Glu281Ala	missense_variant	Exon 8 of 8	1		ENSP00000386353.1
MAT2A	ENST00000481412.5	n.1200A>C		non_coding_transcript_exon_variant	Exon 7 of 7	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 344 of the MAT2A protein (p.Glu344Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with thoracic aortic aneurysm (PMID: 25557781; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265866). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MAT2A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MAT2A function (PMID: 25557781). For these reasons, this variant has been classified as Pathogenic. -

not provided Uncertain:1

Oct 12, 2016

OMIM

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.1	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.064	T;T
Polyphen		0.92	P;.
Vest4		0.86
MutPred		0.57		Loss of disorder (P = 0.034);.;
MVP		0.96
MPC		2.3
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.87
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs886039820; hg19: chr2-85770103;