15-45364854-G-C

Position:

chr15-45364854-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PS3_SupportingPM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.985C>G variant in GATM is a missense variant that is predicted to result in the substitution of leucine by valine at position 329 (p.Leu329Val). This variant was reported as a single heterozygous variant in one control individual, and follow-up functional assays (site-directed mutagenesis in HeLa cells) demonstrated that it resulted in <10% of wild-type enzyme activity (PMID:27233232) (PS3_Supporting). The authors of this report have deposited it in ClinVar (variant ID 225919). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 (2/113682 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.04 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). 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, PM2_Supporting, BP4.(Classification approved by the ClinGen CCDS VCP on December 8, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7542807/MONDO:0012996/025

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

GATM
NM_001482.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.01

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 1 ACMG points.

PS3

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

PM2

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

BP4

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.985C>G	p.Leu329Val	missense_variant	7/9	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.985C>G	p.Leu329Val	missense_variant	7/9	1	NM_001482.3	ENSP00000379895.3		P50440-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251356

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135848

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000137

AC:

AN:

1461602

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Arginine:glycine amidinotransferase deficiency

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Dec 08, 2022

The NM_001482.3:c.985C>G variant in GATM is a missense variant that is predicted to result in the substitution of leucine by valine at position 329 (p.Leu329Val). This variant was reported as a single heterozygous variant in one control individual, and follow-up functional assays (site-directed mutagenesis in HeLa cells) demonstrated that it resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The authors of this report have deposited it in ClinVar (variant ID 225919). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 (2/113682 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.04 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). 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, PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCP on December 8, 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

Benign

0.077

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Benign

0.85

DEOGEN2

Uncertain

0.48

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.025

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.0067

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.50

N;N

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.52

N;N

REVEL

Benign

0.040

Sift

Benign

0.43

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.032

B;B

Vest4

0.28

MVP

0.15

MPC

0.70

ClinPred

0.27

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.53

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