15-45362005-T-C

Variant names:

• chr15-45362005-T-C
• rs886051201
• ENST00000558362.5:n.3032A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.*104A>G variant is a single nucleotide substitution in the 3'UTR of GATM. To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence, and SpliceAI predicts no impact on splicing. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000004811 (2/415744 alleles) in the European non-Finnish population. This is below the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 316208). In summary, this variant meets the criteria to be classified as uncertain significance 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 2.0.0): PM2_Supporting.(Classification approved by the ClinGen CCDS VCEP on April 10, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA10642026/MONDO:0012996/025

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: GATM NM_001482.3 3_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: 1.64
• Publications: 0 publications found

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]

GATM Gene-Disease associations (from GenCC):

• AGAT deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• Fanconi renotubular syndrome 1

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• primary Fanconi syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.*104A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.*104A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_001482.3	ENSP00000379895.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000334 AC: 2 AN: 599274 Hom.: 0 Cov.: 7 AF XY: 0.00000309 AC XY: 1 AN XY: 324016

African (AFR) AF: 0.00 AC: 0 AN: 16524

American (AMR) AF: 0.00 AC: 0 AN: 36578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20250

East Asian (EAS) AF: 0.00 AC: 0 AN: 33004

South Asian (SAS) AF: 0.00 AC: 0 AN: 65116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4078

European-Non Finnish (NFE) AF: 0.00000575 AC: 2 AN: 347732

Other (OTH) AF: 0.00 AC: 0 AN: 32056

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency Uncertain:2

Apr 10, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001482.3:c.*104A>G variant is a single nucleotide substitution in the 3'UTR of GATM. To our knowledge, this variant has not been reported in the literature in an individual with features of AGAT deficiency. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence, and SpliceAI predicts no impact on splicing. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000004811 (2/415744 alleles) in the European non-Finnish population. This is below the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 316208). In summary, this variant meets the criteria to be classified as uncertain significance 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 2.0.0): PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 10, 2025). -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.85
PhyloP100		1.6

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: rs886051201; hg19: chr15-45654203;