19-1401438-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. BP7PM2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.39C>A (p.Gly13=) variant in GAMT is a synonymous variant in exon 1. It is absent in gnomAD v2.1.1 (PM2_Supporting); however, this region has low coverage and, therefore, the allele frequency data may not be accurate. It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant does not appear to have been reported in the published literature. It is noted in ClinVar (Variation ID: 544263). Although this variant may be rare, it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID:25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7.(Classification approved by the ClinGen CCDS VCEP on June 6, 2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA504731736/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GAMT
NM_000156.6 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:3

Conservation

PhyloP100: 0.0100

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 -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.

BP7

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.39C>A	p.Gly13Gly	synonymous_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 link	c.39C>A	p.Gly13Gly	synonymous_variant	Exon 1 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GAMT	ENST00000252288.8 link	c.39C>A	p.Gly13Gly	synonymous_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8 link	c.39C>A	p.Gly13Gly	synonymous_variant	Exon 1 of 5	2		ENSP00000403536.2
GAMT	ENST00000640762.1 link	c.39C>A	p.Gly13Gly	synonymous_variant	Exon 1 of 6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1260138

Hom.:

Cov.:

AF XY:

0.0000324

AC XY:

AN XY:

617538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25642

American (AMR)

AF:

0.00

AC:

AN:

20190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21472

East Asian (EAS)

AF:

0.00

AC:

AN:

27620

South Asian (SAS)

AF:

0.00

AC:

AN:

63184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31558

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3796

European-Non Finnish (NFE)

AF:

0.0000404

AC:

AN:

1014890

Other (OTH)

AF:

0.0000772

AC:

AN:

51786

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

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:

0.0000132

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Oct 10, 2019

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 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of guanidinoacetate methyltransferase

Benign:1

Jun 06, 2022

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.39C>A (p.Gly13=) variant in GAMT is a synonymous variant in exon 1. It is absent in gnomAD v2.1.1 (PM2_Supporting); however, this region has low coverage and, therefore, the allele frequency data may not be accurate. It is predicted to not impact splicing by SpliceAI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant does not appear to have been reported in the published literature. It is noted in ClinVar (Variation ID: 544263). Although this variant may be rare, it has been classified as likely benign by the ClinGen Creatine Deficiency Syndromes (CCDS) Variant Curation Expert Panel (VCEP) based on the recommendation of Richards et al (PMID: 25741868) because it is a synonymous variant, the altered nucleotide is not highly conserved, computational prediction suggests no impact on splicing, and there is no additional evidence to suggest that the variant is disease-causing. GAMT-specific ACMG/AMP criteria applied, as specified by the CCDS VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

0.010

PromoterAI

0.035

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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