15-45364854-G-C

Variant names:

• chr15-45364854-G-C
• rs373802463
• NM_001482.3:c.985C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. BP4 PM2_Supporting PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.985C>G variant in GATM is a missense variant that is predicted to result in the substitution of leucine by valine at position 329 (p.Leu329Val). This variant was reported as a single heterozygous variant in one control individual, and follow-up functional assays (site-directed mutagenesis in HeLa cells) demonstrated that it resulted in <10% of wild-type enzyme activity (PMID:27233232) (PS3_Supporting). The authors of this report have deposited it in ClinVar (variant ID 225919). The highest population minor allele frequency in gnomAD v4.1.0. is 0.000001695 (2/1179822 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.04 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). SpliceAI predicts that the variant has no impact on splicing. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCP on April 11, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7542807/MONDO:0012996/025

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: 4.01
• Publications: 1 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.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	NM_001482.3	MANE Select	c.985C>G	p.Leu329Val	missense	Exon 7 of 9	NP_001473.1
	GATM	NM_001321015.2		c.598C>G	p.Leu200Val	missense	Exon 10 of 12	NP_001307944.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	ENST00000396659.8	TSL:1 MANE Select	c.985C>G	p.Leu329Val	missense	Exon 7 of 9	ENSP00000379895.3
	GATM	ENST00000558362.5	TSL:1	n.2641C>G		non_coding_transcript_exon	Exon 6 of 8
	GATM	ENST00000675701.1		c.925C>G	p.Leu309Val	missense	Exon 7 of 9	ENSP00000502671.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251356 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461602 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727090

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111820

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Arginine:glycine amidinotransferase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.46
CADD	Uncertain	24
DANN	Benign	0.85
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.50	N
PhyloP100		4.0
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.040
Sift	Benign	0.43	T
Sift4G	Benign	0.51	T
Polyphen		0.032	B
Vest4		0.28
MVP		0.15
MPC		0.70
ClinPred		0.27	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.53
Mutation Taster		=69/31	polymorphism

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: rs373802463; hg19: chr15-45657052;