rs10887721

Positions:

• chr10-80285598-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000372213.8(MAT1A):​c.92-9C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,587,578 control chromosomes in the GnomAD database, including 22,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (5159 hom., cov: 32)
  • Exomes 𝑓: 0.14 (17032 hom.)
• Consequence: MAT1A ENST00000372213.8 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.4505
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.300

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 10-80285598-G-C is Benign according to our data. Variant chr10-80285598-G-C is described in ClinVar as [Benign]. Clinvar id is 256108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-80285598-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.44 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.92-9C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.92-9C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000429.3	ENSP00000361287	P1
MAT1A	ENST00000455001.1	c.26-9C>G		splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000414961

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32849 AN: 151980 Hom.: 5144 Cov.: 32

Gnomad AFR AF: 0.446

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0921

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.183

GnomAD3 exomes AF: 0.138 AC: 34758 AN: 251282 Hom.: 3584 AF XY: 0.136 AC XY: 18410 AN XY: 135806

Gnomad AFR exome AF: 0.456

Gnomad AMR exome AF: 0.0758

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.145

Gnomad OTH exome AF: 0.131

GnomAD4 exome AF: 0.142 AC: 203208 AN: 1435480 Hom.: 17032 Cov.: 27 AF XY: 0.140 AC XY: 100100 AN XY: 715876

Gnomad4 AFR exome AF: 0.461

Gnomad4 AMR exome AF: 0.0827

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.000531

Gnomad4 SAS exome AF: 0.103

Gnomad4 FIN exome AF: 0.115

Gnomad4 NFE exome AF: 0.142

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.216 AC: 32893 AN: 152098 Hom.: 5159 Cov.: 32 AF XY: 0.212 AC XY: 15745 AN XY: 74356

Gnomad4 AFR AF: 0.446

Gnomad4 AMR AF: 0.129

Gnomad4 ASJ AF: 0.170

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0914

Gnomad4 FIN AF: 0.111

Gnomad4 NFE AF: 0.142

Gnomad4 OTH AF: 0.180

Alfa AF: 0.171 Hom.: 850

Bravo AF: 0.229

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hepatic methionine adenosyltransferase deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.45
dbscSNV1_RF	Benign	0.37
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: rs10887721; hg19: chr10-82045354;