rs146057680

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4BS1_Supporting

The NM_001482.3(GATM):c.701A>G(p.Asp234Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,614,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 0 hom. )

Consequence

GATM
NM_001482.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4O:1

Conservation

PhyloP100: 7.39

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30924505).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000204 (31/152188) while in subpopulation NFE AF= 0.000426 (29/68032). AF 95% confidence interval is 0.000304. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GATM	NM_001482.3 link	c.701A>G	p.Asp234Gly	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.701A>G	p.Asp234Gly	missense_variant	Exon 5 of 9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000426

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000191

AC:

AN:

251340

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000396

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000253

AC:

370

AN:

1461816

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

176

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000323

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000204

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000426

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000461

Hom.:

Bravo

AF:

0.000193

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Other:1

Oct 02, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate no damaging effect (DesRoches et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27233232) -

Hospital for Sick Children

Significance: not provided

Review Status: no classification provided

Collection Method: in vitro

- -

Inborn genetic diseases

Uncertain:1

Jul 28, 2020

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D234G variant (also known as c.701A>G), located in coding exon 5 of the GATM gene, results from an A to G substitution at nucleotide position 701. The aspartic acid at codon 234 is replaced by glycine, an amino acid with similar properties. In an assay of GATM activity this alteration was found to be functionally normal (DesRoches CL et al. Hum. Mutat., 2016 09;37:926-32). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Arginine:glycine amidinotransferase deficiency

Uncertain:1

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 234 of the GATM protein (p.Asp234Gly). This variant is present in population databases (rs146057680, gnomAD 0.04%). 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: 205624). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GATM protein function. 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. -

Arginine:glycine amidinotransferase deficiency;C4551503:Fanconi renotubular syndrome 1

Uncertain:1

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

D;.;.

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.31

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;M;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

D;N;D

REVEL

Benign

0.27

Sift

Benign

0.056

T;T;D

Sift4G

Uncertain

0.028

D;D;.

Polyphen

0.59

P;P;.

Vest4

0.76

MVP

0.52

MPC

1.0

ClinPred

0.15

GERP RS

5.6

Varity_R

0.40

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over