10-80280766-G-C

Position:

• chr10-80280766-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000429.3(MAT1A):​c.319C>G​(p.Leu107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MAT1A NM_000429.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.89

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.319C>G	p.Leu107Val	missense_variant	4/9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.319C>G	p.Leu107Val	missense_variant	4/9	1	NM_000429.3	ENSP00000361287	P1
MAT1A	ENST00000455001.1	c.130C>G	p.Leu44Val	missense_variant	3/5	5		ENSP00000414961

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251474 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2017

The L107V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to ourknowledge. The L107V variant is not observed in large population cohorts (Lek et al., 2016; 1000 GenomesConsortium et al., 2015; Exome Variant Server). The L107V variant is a conservative amino acid substitution, whichis not likely to impact secondary protein structure as these residues share similar properties. This substitution occursat a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or notthe variant is damaging to the protein structure/function. In summary, based on the currently available information, itis unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hepatic methionine adenosyltransferase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 107 of the MAT1A protein (p.Leu107Val). This variant is present in population databases (no rsID available, gnomAD 0.009%). This missense change has been observed in individual(s) with autosomal recessive hypermethioninemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 418289). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAT1A protein function with a negative predictive value of 80%. 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	0.32
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D
Eigen	Benign	0.039
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N;N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.040	D;D
Polyphen		0.012	B;.
Vest4		0.63
MutPred		0.73		Gain of sheet (P = 0.0477);.;
MVP		0.89
MPC		1.2
ClinPred		0.79	D
GERP RS		3.6
Varity_R		0.78
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1064793166; hg19: chr10-82040522;