rs756268499

Variant names:

• chr2-85539298-A-C
• rs756268499
• NM_005911.6:c.11A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-85539298-A-C
• chr2-85539298-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005911.6(MAT2A):​c.11A>C​(p.Gln4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,451,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MAT2A NM_005911.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58
• Publications: 0 publications found

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]

PARTICL (HGNC:50886): (promoter of MAT2A antisense radiation-induced circulating long non-coding RNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36979955).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT2A	NM_005911.6	c.11A>C	p.Gln4Pro	missense_variant	Exon 1 of 9	ENST00000306434.8	NP_005902.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT2A	ENST00000306434.8	c.11A>C	p.Gln4Pro	missense_variant	Exon 1 of 9	1	NM_005911.6	ENSP00000303147.3
MAT2A	ENST00000465151.5	n.131A>C		non_coding_transcript_exon_variant	Exon 1 of 2	2
MAT2A	ENST00000469221.5	n.131A>C		non_coding_transcript_exon_variant	Exon 1 of 3	2
PARTICL	ENST00000667933.3	n.-188T>G		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000836 AC: 2 AN: 239312 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1451978 Hom.: 0 Cov.: 30 AF XY: 0.00000554 AC XY: 4 AN XY: 722462

African (AFR) AF: 0.00 AC: 0 AN: 32184

American (AMR) AF: 0.00 AC: 0 AN: 43676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 38304

South Asian (SAS) AF: 0.00 AC: 0 AN: 85066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108026

Other (OTH) AF: 0.00 AC: 0 AN: 59898

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Aug 24, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces glutamine with proline at codon 4 of the MAT2A protein (p.Gln4Pro). The glutamine residue is moderately conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is present in population databases (rs756268499, ExAC 0.002%). This variant has not been reported in the literature in individuals with MAT2A-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.014
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.65	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Benign	1.1	L
PhyloP100		2.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	0.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.34	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.19		Gain of catalytic residue at N2 (P = 0.0439);
MVP		0.94
MPC		1.4
ClinPred		0.56	D
GERP RS		4.7
PromoterAI		0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.78
Mutation Taster		=78/22	polymorphism

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: rs756268499; hg19: chr2-85766421;