rs1049518

chr15-45361169-G-Achr15-45361169-G-Cchr15-45361169-G-T

Variant summary

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

The NM_001482.3(GATM):c.*940C>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 0.562 in 151,842 control chromosomes in the GnomAD database, including 27,429 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.56 (27429 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 2.40

Genes affected

GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 15-45361169-G-A is Benign according to our data. Variant chr15-45361169-G-A is described in ClinVar as [Benign]. Clinvar id is 316200.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATM	NM_001482.3	c.*940C>T		3_prime_UTR_variant	9/9	ENST00000396659.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATM	ENST00000396659.8	c.*940C>T		3_prime_UTR_variant	9/9	1	NM_001482.3	P1
GATM	ENST00000558362.5	n.3868C>T		non_coding_transcript_exon_variant	8/8	1
GATM	ENST00000676090.1	c.*2943C>T		3_prime_UTR_variant, NMD_transcript_variant	10/10
GATM	ENST00000675323.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85195 AN: 151724 Hom.: 27374 Cov.: 32

Gnomad AFR AF: 0.843

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.621

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.909

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.558

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.562 AC: 85313 AN: 151842 Hom.: 27429 Cov.: 32 AF XY: 0.569 AC XY: 42192 AN XY: 74174

Gnomad4 AFR AF: 0.843

Gnomad4 AMR AF: 0.621

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.909

Gnomad4 SAS AF: 0.593

Gnomad4 FIN AF: 0.412

Gnomad4 NFE AF: 0.377

Gnomad4 OTH AF: 0.563

Alfa AF: 0.419 Hom.: 16055

Bravo AF: 0.592

Asia WGS AF: 0.736 AC: 2546 AN: 3464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase 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, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_001482.3:c.*940C>T variant is a single nucleotide substitution in the 3'UTR of GATM. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1, in a population with >2000 alleles, is 0.8433 (7330/8692 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). There is a ClinVar entry for this variant (Variation ID: 316200, 1 star review status) with one submitter classifying the variant as benign. In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0, ; classification approved June 6, 2022): BA1. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	6.7
Dann	Benign	0.69

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: rs1049518; hg19: chr15-45653367;