chr15-45361509-T-C

Position:

• chr15-45361509-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.*600A>G 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 continental population with >2000 alleles, is 0.2934 (2554/8704 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: 316206). 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 1.1.0): BA1.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10647042/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.32 (8903 hom., cov: 32)
  • Exomes 𝑓: 0.30 (126 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: 1.85

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 -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATM	NM_001482.3	c.*600A>G		3_prime_UTR_variant	9/9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.*600A>G		3_prime_UTR_variant	9/9	1	NM_001482.3	ENSP00000379895	P1

Frequencies

GnomAD3 genomes AF: 0.320 AC: 48623 AN: 151944 Hom.: 8881 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.179

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.348

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.309

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.295 AC: 678 AN: 2298 Hom.: 126 Cov.: 0 AF XY: 0.307 AC XY: 362 AN XY: 1178

Gnomad4 AFR exome AF: 0.324

Gnomad4 AMR exome AF: 0.543

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.875

Gnomad4 SAS exome AF: 0.423

Gnomad4 FIN exome AF: 0.350

Gnomad4 NFE exome AF: 0.238

Gnomad4 OTH exome AF: 0.326

GnomAD4 genome AF: 0.320 AC: 48670 AN: 152062 Hom.: 8903 Cov.: 32 AF XY: 0.329 AC XY: 24439 AN XY: 74324

Gnomad4 AFR AF: 0.297

Gnomad4 AMR AF: 0.474

Gnomad4 ASJ AF: 0.348

Gnomad4 EAS AF: 0.832

Gnomad4 SAS AF: 0.351

Gnomad4 FIN AF: 0.309

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.345

Alfa AF: 0.207 Hom.: 723

Bravo AF: 0.338

Asia WGS AF: 0.560 AC: 1929 AN: 3454

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Benign:2

Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_001482.3:c.*600A>G 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 continental population with >2000 alleles, is 0.2934 (2554/8704 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: 316206). 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 1.1.0): BA1. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	15
DANN	Benign	0.87

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: rs1049503; hg19: chr15-45653707;