rs11595587

chr10-80289576-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000429.3(MAT1A):c.-153C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 694,976 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.025 (77 hom., cov: 32)
  • Exomes 𝑓: 0.028 (263 hom.)
• Consequence: MAT1A NM_000429.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.127

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-80289576-G-A is Benign according to our data. Variant chr10-80289576-G-A is described in ClinVar as [Benign]. Clinvar id is 301205.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-80289576-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0247 (3757/152120) while in subpopulation NFE AF= 0.0365 (2485/68000). AF 95% confidence interval is 0.0353. There are 77 homozygotes in gnomad4. There are 1828 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 77 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAT1A	NM_000429.3	c.-153C>T		5_prime_UTR_variant	1/9	ENST00000372213.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAT1A	ENST00000372213.8	c.-153C>T		5_prime_UTR_variant	1/9	1	NM_000429.3	P1

Frequencies

GnomAD3 genomes AF: 0.0247 AC: 3754 AN: 152002 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.00611

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0248

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0426

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0365

Gnomad OTH AF: 0.0244

GnomAD4 exome AF: 0.0278 AC: 15075 AN: 542856 Hom.: 263 Cov.: 5 AF XY: 0.0266 AC XY: 7811 AN XY: 294154

Gnomad4 AFR exome AF: 0.00810

Gnomad4 AMR exome AF: 0.0219

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00648

Gnomad4 FIN exome AF: 0.0384

Gnomad4 NFE exome AF: 0.0358

Gnomad4 OTH exome AF: 0.0260

GnomAD4 genome AF: 0.0247 AC: 3757 AN: 152120 Hom.: 77 Cov.: 32 AF XY: 0.0246 AC XY: 1828 AN XY: 74374

Gnomad4 AFR AF: 0.00610

Gnomad4 AMR AF: 0.0248

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0426

Gnomad4 NFE AF: 0.0365

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0339 Hom.: 174

Bravo AF: 0.0231

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hepatic methionine adenosyltransferase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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	-0.70
Cadd	Benign	5.1
Dann	Benign	0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs11595587; hg19: chr10-82049332;