rs374592247

Variant names:

• chr15-45362137-C-T
• rs374592247
• NM_001482.3:c.1244G>A
• GATM p.Arg415Gln

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BA1 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.1244G>A variant in GATM is a missense variant predicted to cause the substitution of an arginine by a glutamine at amino acid position 415 (p.Arg415Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000915 (28/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in 39% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID:27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 225921). 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, BS3_Supporting.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7542752/MONDO:0012996/025

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000092 (2 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 7.31
• 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, 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

Specifications for GATM are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -9 ACMG points.

• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.1244G>A	p.Arg415Gln	missense	Exon 9 of 9	NP_001473.1	P50440-1
	GATM	NM_001321015.2		c.857G>A	p.Arg286Gln	missense	Exon 12 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.1244G>A	p.Arg415Gln	missense	Exon 9 of 9	ENSP00000379895.3	P50440-1
	GATM	ENST00000558362.5	TSL:1	n.2900G>A		non_coding_transcript_exon	Exon 8 of 8
	GATM	ENST00000887717.1		c.1271G>A	p.Arg424Gln	missense	Exon 9 of 9	ENSP00000557776.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152086 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000176 AC: 44 AN: 250552 AF XY: 0.000214

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461396 Hom.: 2 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 727052

African (AFR) AF: 0.0000896 AC: 3 AN: 33466

American (AMR) AF: 0.0000447 AC: 2 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.000881 AC: 76 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 0.0000423 AC: 47 AN: 1111584

Other (OTH) AF: 0.0000828 AC: 5 AN: 60382

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152086 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74310

African (AFR) AF: 0.0000966 AC: 4 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000491

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	1	Arginine:glycine amidinotransferase deficiency (2)
-	1	-	Arginine:glycine amidinotransferase deficiency;C4551503:Fanconi renotubular syndrome 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.20
Sift	Benign	0.061	T
Sift4G	Benign	0.079	T
Varity_R		0.55
gMVP		0.89
Mutation Taster		=46/54	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374592247;

hg19: chr15-45654335;

COSMIC: COSV67540808;

COSMIC: COSV67540808;