chr10-80272689-G-C

Variant names:

• chr10-80272689-G-C
• rs41284062
• NM_000429.3:c.*1092C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000429.3(MAT1A):​c.*1092C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0543 in 152,442 control chromosomes in the GnomAD database, including 294 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (293 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1 hom.)
• Consequence: MAT1A NM_000429.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.169
• Publications: 2 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-80272689-G-C is Benign according to our data. Variant chr10-80272689-G-C is described in ClinVar as [Benign]. Clinvar id is 301159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0812 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAT1A	NM_000429.3	c.*1092C>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000372213.8	NP_000420.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAT1A	ENST00000372213.8	c.*1092C>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_000429.3	ENSP00000361287.3
MAT1A	ENST00000485270.5	n.1792C>G		non_coding_transcript_exon_variant	Exon 3 of 3	2
MAT1A	ENST00000480845.1	n.621-109C>G		intron_variant	Intron 3 of 4	3

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 8280 AN: 152124 Hom.: 293 Cov.: 32

Gnomad AFR AF: 0.0149

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.0474

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0506

Gnomad FIN AF: 0.0487

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0830

Gnomad OTH AF: 0.0645

GnomAD4 exome AF: 0.0350 AC: 7 AN: 200 Hom.: 1 Cov.: 0 AF XY: 0.0321 AC XY: 5 AN XY: 156

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0432 AC: 7 AN: 162

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.0544 AC: 8277 AN: 152242 Hom.: 293 Cov.: 32 AF XY: 0.0524 AC XY: 3901 AN XY: 74446

African (AFR) AF: 0.0148 AC: 616 AN: 41548

American (AMR) AF: 0.0472 AC: 723 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0509 AC: 245 AN: 4818

European-Finnish (FIN) AF: 0.0487 AC: 516 AN: 10606

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0830 AC: 5647 AN: 68010

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0642 Hom.: 38

Bravo AF: 0.0543

Asia WGS AF: 0.0220 AC: 75 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Hepatic methionine adenosyltransferase deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	1.3
DANN	Benign	0.45
PhyloP100		-0.17
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs41284062; hg19: chr10-82032445;