rs377578020

Positions:

chr15-45368180-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PS3_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met). When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID:27233232) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 225915). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PP3.(Classification approved by the ClinGen CCDS VCEP on January 24, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7542898/MONDO:0012996/025

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GATM
NM_001482.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:3O:1

Conservation

PhyloP100: 9.48

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:

GATM (HGNC:):

GATM links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GATM	NM_001482.3 linkuse as main transcript	c.565C>T	p.Arg189Cys	missense_variant	4/9	ENST00000396659.8	NP_001473.1	P50440-1A0A140VK19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GATM	ENST00000396659.8 linkuse as main transcript	c.565C>T	p.Arg189Cys	missense_variant	4/9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251392

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74328

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jan 24, 2023	The NM_001482.3:c.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00006 (1/16246 alleles) in the African population (none of the population data codes are met). When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). There is a ClinVar entry for this variant (Variation ID: 225915). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PP3. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 189 of the GATM protein (p.Arg189Cys). This variant is present in population databases (rs377578020, gnomAD 0.007%). 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: 225915). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATM protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects 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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 19, 2022

- -

not provided

Other:1

not provided, no classification provided

in vitro

Hospital for Sick Children

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.2

M;M;.

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-8.0

D;D;D

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;.

Polyphen

1.0

D;D;.

Vest4

0.98

MVP

0.78

MPC

2.0

ClinPred

1.0

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.98

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