chr15-45362129-A-G

Position:

chr15-45362129-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BA1BP4BP7

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). 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, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA152946/MONDO:0012996/025

Frequency

Genomes: 𝑓 0.56 ( 27386 hom., cov: 31)

Exomes 𝑓: 0.43 ( 149264 hom. )

Consequence

GATM
NM_001482.3 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:15

Conservation

PhyloP100: 4.29

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

BP7

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATM	NM_001482.3 linkuse as main transcript	c.1252T>C	p.Leu418=	synonymous_variant	9/9	ENST00000396659.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATM	ENST00000396659.8 linkuse as main transcript	c.1252T>C	p.Leu418=	synonymous_variant	9/9	1	NM_001482.3	P1	P50440-1

Frequencies

GnomAD3 genomes

AF:

0.560

AC:

85103

AN:

151898

Hom.:

27327

Cov.:

show subpopulations

Gnomad AFR

AF:

0.842

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.619

Gnomad ASJ

AF:

0.534

Gnomad EAS

AF:

0.908

Gnomad SAS

AF:

0.594

Gnomad FIN

AF:

0.409

Gnomad MID

AF:

0.551

Gnomad NFE

AF:

0.376

Gnomad OTH

AF:

0.556

GnomAD3 exomes

AF:

0.536

AC:

134200

AN:

250570

Hom.:

40460

AF XY:

0.520

AC XY:

70501

AN XY:

135520

show subpopulations

Gnomad AFR exome

AF:

0.850

Gnomad AMR exome

AF:

0.720

Gnomad ASJ exome

AF:

0.534

Gnomad EAS exome

AF:

0.919

Gnomad SAS exome

AF:

0.571

Gnomad FIN exome

AF:

0.420

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.482

GnomAD4 exome

AF:

0.431

AC:

627625

AN:

1457486

Hom.:

149264

Cov.:

AF XY:

0.433

AC XY:

313857

AN XY:

725416

show subpopulations

Gnomad4 AFR exome

AF:

0.861

Gnomad4 AMR exome

AF:

0.705

Gnomad4 ASJ exome

AF:

0.536

Gnomad4 EAS exome

AF:

0.931

Gnomad4 SAS exome

AF:

0.566

Gnomad4 FIN exome

AF:

0.413

Gnomad4 NFE exome

AF:

0.373

Gnomad4 OTH exome

AF:

0.474

GnomAD4 genome

AF:

0.561

AC:

85226

AN:

152016

Hom.:

27386

Cov.:

AF XY:

0.567

AC XY:

42152

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.842

Gnomad4 AMR

AF:

0.620

Gnomad4 ASJ

AF:

0.534

Gnomad4 EAS

AF:

0.909

Gnomad4 SAS

AF:

0.592

Gnomad4 FIN

AF:

0.409

Gnomad4 NFE

AF:

0.376

Gnomad4 OTH

AF:

0.560

Alfa

AF:

0.454

Hom.:

9736

Bravo

AF:

0.592

Asia WGS

AF:

0.741

AC:

2573

AN:

3478

EpiCase

AF:

0.396

EpiControl

AF:

0.395

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 84% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 78. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Arginine:glycine amidinotransferase deficiency

Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). 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, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 29, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi renotubular syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

8.5

DANN

Benign

0.72

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

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