rs202225656

Variant names:

• chr15-45366492-G-C
• rs202225656
• NM_001482.3:c.692C>G

Your query was ambiguous. Multiple possible variants found:

• chr15-45366492-G-C
• chr15-45366492-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS3_Supporting BP4 BS1

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.692C>G variant in GATM is a missense variant predicted to cause the substitution of a serine by a cysteine at amino acid position 231 (p.Ser231Cys). To our knowledge, this variant has not be reported in the literature in an individual with AGAT deficiency. The Grpmax Filtering Allele Frequency (95% confidence) in gnomAD v4.1.0. is 0.0002459 (347/1613966 alleles) in the European non-Finnish population. This is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). Expression of the variant in HeLa cells resulted in 100% wild type AGAT activity indicating that this variant does not impact protein function (PMID:27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function. In addition, SpliceAI predicts that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 205616). In summary, this variant meets the criteria to be classified as likely 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 2.0.0): BS1, BS3_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 10, 2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314874/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:3 B:2
• Conservation: PhyloP100: 5.21
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: 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.692C>G	p.Ser231Cys	missense	Exon 5 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.305C>G	p.Ser102Cys	missense	Exon 8 of 12	NP_001307944.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GATM	ENST00000396659.8	TSL:1 MANE Select	c.692C>G	p.Ser231Cys	missense	Exon 5 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.2348C>G		non_coding_transcript_exon	Exon 4 of 8
	GATM	ENST00000887717.1		c.719C>G	p.Ser240Cys	missense	Exon 5 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000995 AC: 25 AN: 251294 AF XY: 0.000125

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: 0.000211

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000220 AC: 322 AN: 1461790 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 147 AN XY: 727204

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.000269 AC: 299 AN: 1111976

Other (OTH) AF: 0.000298 AC: 18 AN: 60390

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41430

American (AMR) AF: 0.000262 AC: 4 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000210 Hom.: 0

Bravo AF: 0.000151

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Arginine:glycine amidinotransferase deficiency (2)
-	1	1	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.2
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.078
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.022	D
Polyphen		0.50	P
Vest4		0.33
MVP		0.20
MPC		0.72
ClinPred		0.17	T
GERP RS		4.7
Varity_R		0.17
gMVP		0.74
Mutation Taster		=68/32	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: rs202225656; hg19: chr15-45658690; COSMIC: COSV99063815; COSMIC: COSV99063815;