rs1057517759

Variant names:

• chr10-80274641-T-A
• rs1057517759
• NM_000429.3:c.964A>T

Your query was ambiguous. Multiple possible variants found:

• chr10-80274641-T-A
• chr10-80274641-T-C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP2 PP3_Strong PP5

The NM_000429.3(MAT1A):​c.964A>T​(p.Ile322Phe) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I322T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.66
• Publications: 6 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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-80274640-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2782962.
• 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, 0.987
• PP5: Variant 10-80274641-T-A is Pathogenic according to our data. Variant chr10-80274641-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 372407.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.964A>T	p.Ile322Phe	missense_variant	Exon 8 of 9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.964A>T	p.Ile322Phe	missense_variant	Exon 8 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000480845.1	n.196A>T		non_coding_transcript_exon_variant	Exon 2 of 5	3
MAT1A	ENST00000485270.5	n.476A>T		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jun 01, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The I322F variant in the MAT1A gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the I322F variant is a conservative amino acid change, this position is conserved across species and two other conservative missense variants at this position (I322M, I322V) have been reported in association with methionine adenosyltransferase I/III (MAT I/III) deficiency (Ubagai et al. 1995; Fernández-Irigoyen et al. 2010). Expression studies found that both the I322M and I322V variants were associated with reduced methionine adenosyltransferase I/III activity (Ubagai et al. 1995; Fernández-Irigoyen et al. 2010). In summary, we interpret I322F to be a pathogenic variant. -

Hepatic methionine adenosyltransferase deficiency Uncertain:1

Feb 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Different missense substitutions at this codon (p.Ile322Val, p.Ile322Met) have been reported in the homozygous state and in combination with another MAT1A variant in individuals affected with MAT1A-deficiency (PMID: 20675163, 7560086). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MAT1A-related disease. ClinVar contains an entry for this variant (Variation ID: 372407). This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with phenylalanine at codon 322 of the MAT1A protein (p.Ile322Phe). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and phenylalanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.020	D
Polyphen		0.20	B
Vest4		0.98
MutPred		0.90		Loss of stability (P = 0.0523);
MVP		0.98
MPC		1.0
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.96
Mutation Taster		=3/97	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: rs1057517759; hg19: chr10-82034397;