rs371511930

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. BP4PM2

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.328-10C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 2. To our knowledge, this variant has not been reported in the literature among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0003385 (10/29542 alleles) in the Ashkenazi Jewish population, followed by 0.0001857 (219/1179100) in the European non-Finnish population, both of which are lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.03 for acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 328349). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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 2.0.0): PM2_Supporting, 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/CA9043721/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

GAMT
NM_000156.6 intron

Scores

Splicing: ADA: 0.0004596

Clinical Significance

Uncertain significance reviewed by expert panel U:2B:3

Conservation

PhyloP100: 0.264

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 Uncertain_significance. Variant got 1 ACMG points.

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
GAMT	NM_000156.6 linkuse as main transcript	c.328-10C>T		intron_variant		ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 linkuse as main transcript	c.328-10C>T		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.328-10C>T		intron_variant		1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000367

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000126

AC:

AN:

245432

Hom.:

AF XY:

0.0000901

AC XY:

AN XY:

133194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.0000971

Gnomad NFE exome

AF:

0.000235

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000148

AC:

216

AN:

1459154

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

115

AN XY:

725740

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000225

Gnomad4 ASJ exome

AF:

0.000384

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000382

Gnomad4 NFE exome

AF:

0.000175

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000177

AC:

AN:

152326

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000368

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000155

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Uncertain:2

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Oct 08, 2024	The NM_000156.6:c.328-10C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 2. To our knowledge, this variant has not been reported in the literature among individuals with GAMT deficiency and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0003385 (10/29542 alleles) in the Ashkenazi Jewish population, followed by 0.0001857 (219/1179100) in the European non-Finnish population, both of which are lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.03 for acceptor loss suggesting that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 328349). In summary, this variant meets the criteria to be classified as a variant of uncertain significance 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 2.0.0): PM2_Supporting, BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on October 8th, 2024). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 24, 2020

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2021

This variant is associated with the following publications: (PMID: 26003046) -

Cerebral creatine deficiency syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

4.3

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00046

dbscSNV1_RF

Benign

0.0060

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