chr15-45376612-T-C

Position:

chr15-45376612-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.277A>G variant in GATM is a missense variant that is predicted to cause the substitution of an isoleucine by a valine at amino acid position 93 (p.Ile93Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (2/16256 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.143 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). Expression of the variant in HeLa cells resulted in 18% of wild type AGAT activity, over than the cutoff for PS3_Supporting (<15%) and less than the cutoff for BS3_Supporting (≥30%), such that no experimental evidence codes are met. There is a ClinVar entry for this variant (Variation ID: 205610). In summary, this variant meets the criteria to be classified as likely 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): BS1, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314862/MONDO:0012996/025

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

GATM
NM_001482.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:3O:1

Conservation

PhyloP100: 2.54

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 Likely_benign. Variant got -5 ACMG points.

BP4

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

BS1

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.277A>G	p.Ile93Val	missense_variant	2/9	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.277A>G	p.Ile93Val	missense_variant	2/9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

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:

0.0000159

AC:

AN:

251488

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.000169

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

Alfa

AF:

0.0000965

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:3Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency

Uncertain:1Benign:1

Likely benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Oct 08, 2024	The NM_001482.3:c.277A>G variant in GATM is a missense variant that is predicted to cause the substitution of an isoleucine by a valine at amino acid position 93 (p.Ile93Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 (2/16256 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.143 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). Expression of the variant in HeLa cells resulted in 18% of wild type AGAT activity, over than the cutoff for PS3_Supporting (<15%) and less than the cutoff for BS3_Supporting (≥30%), such that no experimental evidence codes are met. There is a ClinVar entry for this variant (Variation ID: 205610). In summary, this variant meets the criteria to be classified as likely 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): BS1, BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 93 of the GATM protein (p.Ile93Val). This variant is present in population databases (rs34991226, 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: 205610). 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 not expected to disrupt GATM protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 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. -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2018

This alteration is classified as likely 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. -

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

Benign

0.048

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.8

DANN

Benign

0.57

DEOGEN2

Benign

0.27

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0062

MetaRNN

Benign

0.035

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

N;N

PrimateAI

Benign

0.37

PROVEAN

Benign

0.52

N;N

REVEL

Benign

0.14

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.13

MVP

0.082

MPC

0.57

ClinPred

0.0095

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.41

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