Genetic Variant NM_001482.3:c.*104A>G (chr15-45362005-T-C) – ACMG Classification: Uncertain_significance (1 pts)

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

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:2

Conservation

PhyloP100: 1.64

Publications

0 publications found

Variant links:

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: Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi renotubular syndrome 1
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
primary Fanconi syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GATM links:

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ACMG classification

Classification was made for transcript

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

PM2

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001482.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	NM_001482.3	MANE Select	c.*104A>G		3_prime_UTR	Exon 9 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.*104A>G		3_prime_UTR	Exon 12 of 12	NP_001307944.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GATM	ENST00000396659.8	TSL:1 MANE Select	c.*104A>G	3_prime_UTR	Exon 9 of 9	ENSP00000379895.3	P50440-1
GATM	ENST00000558362.5	TSL:1	n.3032A>G	non_coding_transcript_exon	Exon 8 of 8
GATM	ENST00000887717.1		c.*104A>G	3_prime_UTR	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000334

AC:

AN:

599274

Hom.:

Cov.:

AF XY:

0.00000309

AC XY:

AN XY:

324016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16524

American (AMR)

AF:

0.00

AC:

AN:

36578

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20250

East Asian (EAS)

AF:

0.00

AC:

AN:

33004

South Asian (SAS)

AF:

0.00

AC:

AN:

65116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43936

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4078

European-Non Finnish (NFE)

AF:

0.00000575

AC:

AN:

347732

Other (OTH)

AF:

0.00

AC:

AN:

32056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arginine:glycine amidinotransferase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over