19-1398912-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1BP4

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.570+4C>T variant in GAMT is an intronic variant affecting a nucleotide within the consensus splice site of intron 5. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. The highest population frequency in gnomAD v4.1.0. is 0.001148 (86/74912 alleles; no homozygotes) in the African / African American population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.001), and therefore meets this criterion (BS1). The computational splicing predictor SpliceAI gives a score of 0.01 for donor loss and suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 582572). In summary, this variant meets the criteria to be classified as likely benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): BS1, BP4.(Classification approved by the ClinGen Creatine Deficiency Syndromes Variant Curation Expert Panel on April 16, 2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043611/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

GAMT
NM_138924.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:2

Conservation

PhyloP100: -1.55

Publications

2 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

GAMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

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

BS1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138924.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.570+4C>T		splice_region intron	N/A	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.574C>T	p.Arg192Cys	missense	Exon 5 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAMT	ENST00000252288.8	TSL:1 MANE Select	c.570+4C>T		splice_region intron	N/A	ENSP00000252288.1	Q14353-1
GAMT	ENST00000447102.8	TSL:2	c.574C>T	p.Arg192Cys	missense	Exon 5 of 5	ENSP00000403536.2	Q14353-2
GAMT	ENST00000902474.1		c.840+4C>T		splice_region intron	N/A	ENSP00000572533.1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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

GnomAD2 exomes

AF:

0.0000839

AC:

AN:

250176

AF XY:

0.0000590

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460992

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111982

Other (OTH)

AF:

0.0000497

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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:

0.000355

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41432

American (AMR)

AF:

0.000327

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

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:

0.000211

Hom.:

Bravo

AF:

0.000506

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Deficiency of guanidinoacetate methyltransferase (3)

Cerebral creatine deficiency syndrome (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.39

CADD

Benign

0.036

(source)

DANN

Benign

0.71

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.41

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.023

MetaSVM

Uncertain

-0.18

PhyloP100

-1.6

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.20

REVEL

Uncertain

0.35

Sift

Uncertain

0.0030

Sift4G

Benign

0.077

Vest4

0.063

MVP

0.46

MPC

0.20

ClinPred

0.021

GERP RS

-6.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.61

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over