rs7087728

Positions:

• chr10-80273714-G-A
• chr10-80273714-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000429.3(MAT1A):​c.*67C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,141,262 control chromosomes in the GnomAD database, including 22,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3780 hom., cov: 32)
  • Exomes 𝑓: 0.19 (18839 hom.)
• Consequence: MAT1A NM_000429.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.70

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-80273714-G-A is Benign according to our data. Variant chr10-80273714-G-A is described in ClinVar as [Benign]. Clinvar id is 301184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAT1A	NM_000429.3	c.*67C>T		3_prime_UTR_variant	9/9	ENST00000372213.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAT1A	ENST00000372213.8	c.*67C>T		3_prime_UTR_variant	9/9	1	NM_000429.3	P1
MAT1A	ENST00000480845.1	n.487C>T		non_coding_transcript_exon_variant	3/5	3
MAT1A	ENST00000485270.5	n.767C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32253 AN: 151942 Hom.: 3763 Cov.: 32

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.271

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.0182

Gnomad SAS AF: 0.287

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.221

GnomAD4 exome AF: 0.185 AC: 183491 AN: 989202 Hom.: 18839 Cov.: 13 AF XY: 0.188 AC XY: 96636 AN XY: 512968

Gnomad4 AFR exome AF: 0.287

Gnomad4 AMR exome AF: 0.298

Gnomad4 ASJ exome AF: 0.235

Gnomad4 EAS exome AF: 0.0209

Gnomad4 SAS exome AF: 0.279

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.212 AC: 32306 AN: 152060 Hom.: 3780 Cov.: 32 AF XY: 0.211 AC XY: 15689 AN XY: 74318

Gnomad4 AFR AF: 0.283

Gnomad4 AMR AF: 0.272

Gnomad4 ASJ AF: 0.248

Gnomad4 EAS AF: 0.0182

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.134

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.224

Alfa AF: 0.168 Hom.: 1902

Bravo AF: 0.222

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hepatic methionine adenosyltransferase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.39
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7087728; hg19: chr10-82033470; COSMIC: COSV64745030; COSMIC: COSV64745030;