rs1441030187

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PP4_StrongPP3PM2_SupportingPS3PM3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.224C>T variant in GAMT is a missense variant that is predicted to result in the substitution of alanine by valine at amino acid 75 (p.Ala75Val). One patient, with mild intellectual disability, anti-epileptic drug-responsive seizures, and stereotypic movements has been reported with creatine and guanidinoacetate peak absent on MRS, bilateral thalami increased on MRI, and urine guanidinoacetate levels between 1.1 and 12 times above the upper limit of reference range (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00007 (1/15028 alleles) in the African population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). GAMT-deficient fibroblasts transfected with the variant showed <15% wild-type enzyme activity (PMID:24415674). The computational predictor REVEL gives a score of 0.86 which is above the threshold of 0.75, evidence that correlates with impact to GAMT function (PP3). There is a ClinVar entry for this variant (Variation ID: 544251). In summary, this variant meets the criteria to be classified as pathogenic for GAMT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): PP4_Strong, PP3, PS3_Supporting, PM2_Supporting, PM3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA402996954/MONDO:0012999/026

Frequency

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

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

7

11

Clinical Significance

Pathogenic reviewed by expert panel P:6U:2

Conservation

PhyloP100: 9.88

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

GAMT links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

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

PM2

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

PM3

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. 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.224C>T	p.Ala75Val	missense	Exon 2 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.224C>T	p.Ala75Val	missense	Exon 2 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.224C>T	p.Ala75Val	missense	Exon 2 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.494C>T	p.Ala165Val	missense	Exon 2 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.224C>T	p.Ala75Val	missense	Exon 2 of 5	ENSP00000403536.2	Q14353-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152190

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

GnomAD2 exomes

AF:

0.0000209

AC:

5

AN:

239744

AF XY:

0.0000230

show subpopulations

Gnomad AFR exome

AF:

0.0000665

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:

0.0000278

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

42

AN:

1456236

Hom.:

0

Cov.:

33

AF XY:

0.0000318

AC XY:

23

AN XY:

723922

show subpopulations

African (AFR)

AF:

0.0000898

AC:

3

AN:

33422

American (AMR)

AF:

0.00

AC:

0

AN:

44228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

0

AN:

39544

South Asian (SAS)

AF:

0.0000704

AC:

6

AN:

85188

European-Finnish (FIN)

AF:

0.00

AC:

0

AN:

51626

Middle Eastern (MID)

AF:

0.00

AC:

0

AN:

5758

European-Non Finnish (NFE)

AF:

0.0000288

AC:

32

AN:

1110288

Other (OTH)

AF:

0.0000166

AC:

1

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0

3

6

10

13

16

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

0

2

4

6

8

10

<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:

0.00000657

AC:

1

AN:

152190

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

0

AN:

41444

American (AMR)

AF:

0.00

AC:

0

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

0

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

0

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

0

AN:

4832

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:

68022

Other (OTH)

AF:

0.00

AC:

0

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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:

0.0000264

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

5

1

-

Deficiency of guanidinoacetate methyltransferase (6)

1

1

-

Cerebral creatine deficiency syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.073

D

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

28

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.97

D

LIST_S2

Uncertain

0.93

D

M_CAP

Pathogenic

0.51

D

MetaRNN

Pathogenic

0.88

D

MetaSVM

Uncertain

0.65

D

MutationAssessor

Pathogenic

3.2

M

PhyloP100

9.9

PrimateAI

Uncertain

0.56

T

PROVEAN

Uncertain

-3.3

D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.0030

D

Sift4G

Uncertain

0.029

D

Polyphen

1.0

D

Vest4

0.97

MutPred

0.50

Gain of catalytic residue at A75 (P = 0.0098)

MVP

0.93

MPC

0.63

ClinPred

0.87

D

GERP RS

3.2

PromoterAI

-0.017

Neutral

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.71

gMVP

0.87

Mutation Taster

=7/93

disease causing

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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: rs1441030187; hg19: chr19-1399895; COSMIC: COSV52040506; COSMIC: COSV52040506; API