rs192416474

Positions:

chr19-1399202-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BA1BP4BS2

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.392-7C>T variant in GAMT is a nucleotide substitution in intron 3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00430 (107/24892 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 4 homozygotes in gnomAD v2.1.1 (all in the S Asian population) which, given the early onset and severity of phenotype for GAMT deficiency, supporting that the variant is not associated with GAMT deficiency. Computational evidence from SpliceAI and varSEAK suggests no impact on the gene/gene product (BP4). There is a ClinVar entry for this variant (Variation ID: 137436,). 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 1.1.0): BA1, BS2, BP4.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291019/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.0015 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 8 hom. )

Consequence

GAMT
NM_000156.6 splice_region, intron

Scores

Splicing: ADA: 0.00003445

Clinical Significance

Benign reviewed by expert panel B:8

Conservation

PhyloP100: -1.99

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

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

BS2

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.392-7C>T		splice_region_variant, intron_variant		ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 linkuse as main transcript	c.392-7C>T		splice_region_variant, intron_variant			NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 linkuse as main transcript	c.392-7C>T		splice_region_variant, intron_variant		1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

221

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00456

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000662

AC:

166

AN:

250786

Hom.:

AF XY:

0.000736

AC XY:

100

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00426

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000383

AC:

559

AN:

1461118

Hom.:

Cov.:

AF XY:

0.000453

AC XY:

329

AN XY:

726880

show subpopulations

Gnomad4 AFR exome

AF:

0.00493

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00276

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000944

Gnomad4 OTH exome

AF:

0.000596

GnomAD4 genome

AF:

0.00145

AC:

221

AN:

152294

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

112

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00455

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00352

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000752

Hom.:

Bravo

AF:

0.00128

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 10, 2017	- -

Deficiency of guanidinoacetate methyltransferase

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 05, 2020	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.392-7C>T variant in GAMT is a nucleotide substitution in intron 3. The highest population minor allele frequency in gnomAD v2.1.1 is 0.00430 (107/24892 alleles) in the African population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 4 homozygotes in gnomAD v2.1.1 (all in the S Asian population) which, given the early onset and severity of phenotype for GAMT deficiency, supporting that the variant is not associated with GAMT deficiency. Computational evidence from SpliceAI and varSEAK suggests no impact on the gene/gene product (BP4). There is a ClinVar entry for this variant (Variation ID: 137436,). 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 1.1.0): BA1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

GAMT: BP4, BS2 -

Cerebral creatine deficiency syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.18

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000034

dbscSNV1_RF

Benign

0.0

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