rs774144200

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM5PP4_StrongPP3PM2_SupportingPM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID:19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015).(Classification approved by the ClinGen CCDS VCEP on March 23, 2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA402995388/MONDO:0012999/026

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

12

6

1

Clinical Significance

Likely pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 6.05

Publications

3 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_pathogenic. The variant received 9 ACMG points.

PM2

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

PM3

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

PM5

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

PP3

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

PP4

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.403G>T	p.Asp135Tyr	missense_variant	Exon 4 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 link	c.403G>T	p.Asp135Tyr	missense_variant	Exon 4 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 link	c.403G>T	p.Asp135Tyr	missense_variant	Exon 4 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152196

Hom.:

0

Cov.:

32

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461284

Hom.:

0

Cov.:

34

AF XY:

0.00000138

AC XY:

1

AN XY:

726960

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

0

AN:

33480

American (AMR)

AF:

0.00

AC:

0

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

1

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

52874

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

0

AN:

1111986

Other (OTH)

AF:

0.00

AC:

0

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

1

AN:

152196

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74346

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

0

AN:

41436

American (AMR)

AF:

0.00

AC:

0

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

1

AN:

68032

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0

0

1

1

2

2

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

0

Bravo

AF:

0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase

Pathogenic:2

Dec 13, 2023

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 23, 2023

ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000156.6:c.403G>T (p.Asp135Tyr) variant in GAMT has been identified in one individual with guanidinoacetate methyltransferase deficiency (PMID: 19027335). This variant was identified in 0.001470% (1/68032) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD) (PM2_Supporting). The patient previously reported was a reported compound heterozygote that carried a pathogenic variant, c.507_521dup15 (p.C169_S173dup; ClinVar Variation ID: 431959), in unknown phase (PM3_Supporting). This individual showed reduced creatine peak on brain magnetic resonance spectroscopy and elevated plasma GAA with low creatine with full GAMT gene sequencing (PP4_Strong). The p.Asp135Tyr variant is a missense variant that is predicted damaging by in-silico missense predictors (REVEL score 0.938) (PP3). A different missense variant at the same amino acid residue, p.Asp135Asn, has been previously reported pathogenic (ClinVar Variation ID: 573140) (PM5). In summary, this variant meets criteria to be classified as likely pathogenic for guanidinoacetate methyltransferase (GAMT) deficiency. GAMT-specific ACMG/AMP Criteria applied, as specified by the ClinGen Cerebral Creatine Deficiencies Variant Curation Expert Panel (CCDS VCEP) (Specifications version 1.1.0): PM2_Supporting, PM3_Supporting, PM5, PP3, PP4_Strong (Richards 2015). (Classification approved by the ClinGen CCDS VCEP on March 23, 2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.54

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

29

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.92

D;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.81

D

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.8

H;.;H

PhyloP100

6.1

PrimateAI

Pathogenic

0.80

T

PROVEAN

Pathogenic

-7.9

D;.;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0020

D;.;D

Polyphen

1.0

D;.;.

Vest4

0.99

MutPred

0.89

Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.99

MPC

0.71

ClinPred

1.0

D

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.96

gMVP

0.96

Mutation Taster

=6/94

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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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Other links and lift over

dbSNP: rs774144200; hg19: chr19-1399183; API