chr19-1397489-A-G

Position:

chr19-1397489-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6(GAMT):c.581T>C variant in GAMT is a missense variant predicted to cause substitution of valine by alanine at amino acid 194 (p.Val194Ala). Population allele frequency of this variant is higher than 0.3% in two populations in gnomAD v2.1.1 (BA1 met). In silico predictors predict no damaging effect (REVEL<0.5) and no effect on splicing (SpliceAI<0.05; varSEAK - class 1). To our knowledge, this variant has not been reported in the literature in any individuals with GAMT deficiency. In summary, this variant meets the criteria to be classified as Benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1, BP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA314855/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 3 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:9

Conservation

PhyloP100: 7.14

Variant links:

Genes affected

GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]

GAMT links:

GAMT (HGNC:):

GAMT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

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

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6 linkuse as main transcript	c.581T>C	p.Val194Ala	missense_variant	6/6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.581T>C	p.Val194Ala	missense_variant	6/6	1	NM_000156.6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000640762.1 linkuse as main transcript	c.512T>C	p.Val171Ala	missense_variant	6/6	5		ENSP00000492031.1	A0A1W2PR36
GAMT	ENST00000640164.1 linkuse as main transcript	n.414T>C		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.000787

AC:

191

AN:

242794

Hom.:

AF XY:

0.000733

AC XY:

AN XY:

132300

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000197

Gnomad NFE exome

AF:

0.000624

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.000949

AC:

1379

AN:

1452498

Hom.:

Cov.:

AF XY:

0.000881

AC XY:

637

AN XY:

722932

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00329

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000451

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.000895

GnomAD4 genome

AF:

0.000807

AC:

123

AN:

152340

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00274

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.000876

Hom.:

Bravo

AF:

0.00111

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000669

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000474

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	GAMT: BP4, BS2 -

Deficiency of guanidinoacetate methyltransferase

Uncertain:1Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 21, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jan 30, 2023	The NM_000156.6(GAMT):c.581T>C variant in GAMT is a missense variant predicted to cause substitution of valine by alanine at amino acid 194 (p.Val194Ala). Population allele frequency of this variant is higher than 0.3% in two populations in gnomAD v2.1.1 (BA1 met). In silico predictors predict no damaging effect (REVEL<0.5) and no effect on splicing (SpliceAI<0.05; varSEAK - class 1). To our knowledge, this variant has not been reported in the literature in any individuals with GAMT deficiency. In summary, this variant meets the criteria to be classified as Benign for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.0): BA1, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 22, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 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. -

Cerebral creatine deficiency syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

GAMT-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;.

Eigen

Benign

0.14

Eigen_PC

Benign

0.19

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.80

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.7

M;.

PROVEAN

Benign

-1.7

N;.

REVEL

Uncertain

0.50

Sift

Benign

0.14

T;.

Sift4G

Benign

0.14

T;.

Polyphen

0.72

P;.

Vest4

0.52

MVP

0.83

ClinPred

0.055

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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