NM_000156.6:c.396C>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP7BS2BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.396C>A variant in GAMT is a synonymous (silent) variant (p.Ile132=) with no predicted impact on splicing based on the computational predictor, SpliceAI (BP4, BP7). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles; one homozygote) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher, at 0.00304 (90/29608), this allele frequency data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID:30311383). There is a ClinVar entry for this variant (Variation ID: 328348). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7.(Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043674/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

GAMT
NM_000156.6 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:5

Conservation

PhyloP100: 1.61

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

guanidinoacetate methyltransferase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

GAMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

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

BP7

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6 link	c.396C>A	p.Ile132Ile	synonymous_variant	Exon 4 of 6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 link	c.396C>A	p.Ile132Ile	synonymous_variant	Exon 4 of 5		NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 link	c.396C>A	p.Ile132Ile	synonymous_variant	Exon 4 of 6	1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000124

AC:

AN:

250928

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00239

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461258

Hom.:

Cov.:

AF XY:

0.0000935

AC XY:

AN XY:

726952

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00314

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52830

Middle Eastern (MID)

AF:

0.000693

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1111982

Other (OTH)

AF:

0.000215

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00144

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000215

Hom.:

Bravo

AF:

0.0000604

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Uncertain:1Benign:2

Jun 18, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 18, 2025

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Likely benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000156.6:c.396C>A variant in GAMT is a synonymous (silent) variant (p.Ile132=) with no predicted impact on splicing based on the computational predictor, SpliceAI (BP4, BP7). To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population minor allele frequency in gnomAD v4.1.0. is 0.0006575 (24/10058 alleles; one homozygote) in the Middle Eastern population, which is higher than the PM2_supporting threshold (<0.0004) and lower than the BS1 threshold (>0.001) set by the ClinGen CCDS VCEP (no population codes are met). While the allele frequency in the Ashkenazi Jewish population is higher, at 0.00304 (90/29608), this allele frequency data is not counted because the Ashkenazi Jewish population is not a continental population (see Ghosh et al, 2018, PMID: 30311383). There is a ClinVar entry for this variant (Variation ID: 328348). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency based on the GAMT-specific ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 2.0.0): BP4, BP7. (Classification approved by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel on March 18, 2025) -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:2

Feb 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 17, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cerebral creatine deficiency syndrome

Benign:1

Jul 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

7.8

(source)

DANN

Benign

0.80

PhyloP100

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over