rs1288775

chr15-45369480-T-Achr15-45369480-T-Cchr15-45369480-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001482.3(GATM):c.330A>T(p.Gln110His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,390 control chromosomes in the GnomAD database, including 107,927 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.46 (20539 hom., cov: 32)
  • Exomes 𝑓: 0.31 (87388 hom.)
• Consequence: GATM NM_001482.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.94

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.735975E-7).
• BP6: Variant 15-45369480-T-A is Benign according to our data. Variant chr15-45369480-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 129138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45369480-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.815 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GATM	NM_001482.3	c.330A>T	p.Gln110His	missense_variant	3/9	ENST00000396659.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GATM	ENST00000396659.8	c.330A>T	p.Gln110His	missense_variant	3/9	1	NM_001482.3	P1

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70125 AN: 152004 Hom.: 20476 Cov.: 32

Gnomad AFR AF: 0.786

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.516

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.836

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.439

GnomAD3 exomes AF: 0.421 AC: 105856 AN: 251160 Hom.: 27832 AF XY: 0.400 AC XY: 54283 AN XY: 135768

Gnomad AFR exome AF: 0.793

Gnomad AMR exome AF: 0.652

Gnomad ASJ exome AF: 0.352

Gnomad EAS exome AF: 0.830

Gnomad SAS exome AF: 0.395

Gnomad FIN exome AF: 0.313

Gnomad NFE exome AF: 0.269

Gnomad OTH exome AF: 0.367

GnomAD4 exome AF: 0.314 AC: 459387 AN: 1461268 Hom.: 87388 Cov.: 35 AF XY: 0.314 AC XY: 228182 AN XY: 726946

Gnomad4 AFR exome AF: 0.804

Gnomad4 AMR exome AF: 0.635

Gnomad4 ASJ exome AF: 0.349

Gnomad4 EAS exome AF: 0.847

Gnomad4 SAS exome AF: 0.389

Gnomad4 FIN exome AF: 0.309

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.462 AC: 70246 AN: 152122 Hom.: 20539 Cov.: 32 AF XY: 0.466 AC XY: 34627 AN XY: 74374

Gnomad4 AFR AF: 0.786

Gnomad4 AMR AF: 0.516

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.836

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.308

Gnomad4 NFE AF: 0.261

Gnomad4 OTH AF: 0.446

Alfa AF: 0.288 Hom.: 5456

Bravo AF: 0.497

TwinsUK AF: 0.254 AC: 943

ALSPAC AF: 0.259 AC: 997

ESP6500AA AF: 0.763 AC: 3354

ESP6500EA AF: 0.267 AC: 2297

ExAC AF: 0.418 AC: 50750

Asia WGS AF: 0.629 AC: 2183 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.274

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arginine:glycine amidinotransferase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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. -

not provided Benign:2

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	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
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	11
Dann	Benign	0.77
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.040	T;T;T
MetaRNN	Benign	5.7e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.63	N;N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Benign	0.078
Sift	Benign	0.56	T;T;T
Sift4G	Benign	0.54	T;T;.
Polyphen		0.0	B;B;.
Vest4		0.14
MutPred		0.12		Gain of disorder (P = 0.0912);Gain of disorder (P = 0.0912);.;
MPC		0.64
ClinPred		0.00063	T
GERP RS		3.5
Varity_R		0.054
gMVP		0.58

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

Other links and lift over

dbSNP: rs1288775; hg19: chr15-45661678; COSMIC: COSV67540548; COSMIC: COSV67540548;