rs118204004

Variant names:

• chr10-80275054-A-G
• rs118204004
• NM_000429.3:c.914T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95
• Publications: 8 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain 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 VariationId is 1205.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAT1A	NM_000429.3	MANE Select	c.914T>C	p.Leu305Pro	missense	Exon 7 of 9	NP_000420.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAT1A	ENST00000372213.8	TSL:1 MANE Select	c.914T>C	p.Leu305Pro	missense	Exon 7 of 9	ENSP00000361287.3
	MAT1A	ENST00000480845.1	TSL:3	n.146T>C		non_coding_transcript_exon	Exon 1 of 5
	MAT1A	ENST00000485270.5	TSL:2	n.426T>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1413010 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 698502

African (AFR) AF: 0.00 AC: 0 AN: 32140

American (AMR) AF: 0.00 AC: 0 AN: 37376

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25304

East Asian (EAS) AF: 0.00 AC: 0 AN: 36708

South Asian (SAS) AF: 0.00 AC: 0 AN: 80388

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4858

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087576

Other (OTH) AF: 0.00 AC: 0 AN: 58496

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hepatic methionine adenosyltransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		8.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.93		Gain of catalytic residue at L305 (P = 0.0047)
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs118204004; hg19: chr10-82034810;