rs202225656

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BS3_SupportingBP4BS1

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

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:2

Conservation

PhyloP100: 5.21

Publications

4 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: 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

GATM links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3 link	c.692C>G	p.Ser231Cys	missense_variant	Exon 5 of 9	ENST00000396659.8	NP_001473.1	P50440-1A0A140VK19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8 link	c.692C>G	p.Ser231Cys	missense_variant	Exon 5 of 9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

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:

AN:

251294

AF XY:

0.000125

show subpopulations

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.:

Cov.:

AF XY:

0.000202

AC XY:

147

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.000269

AC:

299

AN:

1111976

Other (OTH)

AF:

0.000298

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41430

American (AMR)

AF:

0.000262

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000210

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Feb 20, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 27233232) -

Arginine:glycine amidinotransferase deficiency

Uncertain:1Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GATM protein (p.Ser231Cys). This variant is present in population databases (rs202225656, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 205616). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GATM protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect GATM function (PMID: 27233232). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 10, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

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). -

Inborn genetic diseases

Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Unlikely to be causative of GATM-related Fanconi renotubular syndrome (AD) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;.;.

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Benign

0.0087

MetaRNN

Benign

0.21

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

5.2

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.1

N;N;N

REVEL

Benign

0.078

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.022

D;D;.

Polyphen

0.50

P;P;.

Vest4

0.33

MVP

0.20

MPC

0.72

ClinPred

0.17

GERP RS

4.7

Varity_R

0.17

gMVP

0.74

Mutation Taster

=68/32

polymorphism

(source)

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over