15-45361374-C-CTG

Position:

• chr15-45361374-C-CTG

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.*734_*735insCA variant inserts two nucleotides 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 0.8397 (7277/8666 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: 316203). 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/CA10636071/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.56 (27212 hom., cov: 0)
  • Exomes 𝑓: 0.67 (1 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: 2.32

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.*734_*735insCA		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.*734_*735insCA		3_prime_UTR_variant	9/9	1	NM_001482.3	ENSP00000379895	P1

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84775 AN: 151520 Hom.: 27157 Cov.: 0

Gnomad AFR AF: 0.840

Gnomad AMI AF: 0.233

Gnomad AMR AF: 0.619

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.908

Gnomad SAS AF: 0.595

Gnomad FIN AF: 0.408

Gnomad MID AF: 0.552

Gnomad NFE AF: 0.376

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.667 AC: 4 AN: 6 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 1 AN XY: 2

Gnomad4 NFE exome AF: 0.667

GnomAD4 genome AF: 0.560 AC: 84893 AN: 151636 Hom.: 27212 Cov.: 0 AF XY: 0.566 AC XY: 41959 AN XY: 74068

Gnomad4 AFR AF: 0.840

Gnomad4 AMR AF: 0.619

Gnomad4 ASJ AF: 0.534

Gnomad4 EAS AF: 0.908

Gnomad4 SAS AF: 0.594

Gnomad4 FIN AF: 0.408

Gnomad4 NFE AF: 0.376

Gnomad4 OTH AF: 0.562

Alfa AF: 0.300 Hom.: 721

Bravo AF: 0.592

Asia WGS AF: 0.738 AC: 2545 AN: 3454

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	Jun 14, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_001482.3:c.*734_*735insCA variant inserts two nucleotides 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 0.8397 (7277/8666 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: 316203). 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). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs35410548; hg19: chr15-45653572;