rs144630886

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP7BA1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.279C>T (p.Asp93=) is a synonymous variant in GAMT that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00484 (87/17976 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). This variant does not appear to have been previously reported in the published literature. It is noted in ClinVar (Variation ID 137434). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BA1, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA291015/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 1 hom. )

Consequence

GAMT
NM_000156.6 synonymous

Scores

Clinical Significance

Benign reviewed by expert panel B:9

Conservation

PhyloP100: -1.20

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: Benign. The variant received -10 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.

BA1

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.279C>T	p.Asp93Asp	synonymous_variant	Exon 2 of 6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 link	c.279C>T	p.Asp93Asp	synonymous_variant	Exon 2 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.279C>T	p.Asp93Asp	synonymous_variant	Exon 2 of 6	1	NM_000156.6	ENSP00000252288.1		Q14353-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00405

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000579

AC:

126

AN:

217640

AF XY:

0.000526

show subpopulations

Gnomad AFR exome

AF:

0.0000759

Gnomad AMR exome

AF:

0.0000953

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00457

Gnomad FIN exome

AF:

0.0000552

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000258

AC:

372

AN:

1442596

Hom.:

Cov.:

AF XY:

0.000257

AC XY:

184

AN XY:

715952

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33136

American (AMR)

AF:

0.0000711

AC:

AN:

42168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25672

East Asian (EAS)

AF:

0.00239

AC:

AN:

38838

South Asian (SAS)

AF:

0.000228

AC:

AN:

83318

European-Finnish (FIN)

AF:

0.0000593

AC:

AN:

50556

Middle Eastern (MID)

AF:

0.000870

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000198

AC:

219

AN:

1103510

Other (OTH)

AF:

0.000486

AC:

AN:

59654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

115

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:

0.000302

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.000131

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00387

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

68024

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

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:

0.000262

Hom.:

Bravo

AF:

0.000442

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GAMT: BP4, BP7 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

May 19, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 26, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of guanidinoacetate methyltransferase

Benign:2

Jun 06, 2022

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000156.6:c.279C>T (p.Asp93=) is a synonymous variant in GAMT that is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00484 (87/17976 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). This variant does not appear to have been previously reported in the published literature. It is noted in ClinVar (Variation ID 137434). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): BA1, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 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. -

Inborn genetic diseases

Benign:1

Dec 29, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: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

-0.49

CADD

Benign

0.88

(source)

DANN

Benign

0.94

PhyloP100

-1.2

PromoterAI

0.10

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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