NM_001482.3:c.330A>T

Variant names:

• chr15-45369480-T-A
• rs1288775
• NM_001482.3:c.330A>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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:17
• Conservation: PhyloP100: 1.94
• Publications: 52 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: 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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 129138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GATM	NM_001482.3	c.330A>T	p.Gln110His	missense_variant	Exon 3 of 9	ENST00000396659.8	NP_001473.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8	c.330A>T	p.Gln110His	missense_variant	Exon 3 of 9	1	NM_001482.3	ENSP00000379895.3

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

GnomAD2 exomes AF: 0.421 AC: 105856 AN: 251160 AF XY: 0.400

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 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

African (AFR) AF: 0.804 AC: 26896 AN: 33470

American (AMR) AF: 0.635 AC: 28413 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9131 AN: 26130

East Asian (EAS) AF: 0.847 AC: 33601 AN: 39688

South Asian (SAS) AF: 0.389 AC: 33571 AN: 86242

European-Finnish (FIN) AF: 0.309 AC: 16525 AN: 53398

Middle Eastern (MID) AF: 0.363 AC: 2092 AN: 5768

European-Non Finnish (NFE) AF: 0.259 AC: 287810 AN: 1111472

Other (OTH) AF: 0.354 AC: 21348 AN: 60380

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

African (AFR) AF: 0.786 AC: 32637 AN: 41514

American (AMR) AF: 0.516 AC: 7887 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1210 AN: 3470

East Asian (EAS) AF: 0.836 AC: 4329 AN: 5178

South Asian (SAS) AF: 0.408 AC: 1966 AN: 4824

European-Finnish (FIN) AF: 0.308 AC: 3250 AN: 10558

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.261 AC: 17773 AN: 67986

Other (OTH) AF: 0.446 AC: 943 AN: 2116

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 76% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 71. Only high quality variants are reported. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 21, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Arginine:glycine amidinotransferase deficiency Benign:5

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

Apr 20, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 29, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jan 08, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.
PhyloP100		1.9
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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