rs372260609

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PM2_SupportingBP4BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000156.6:c.471T>G variant in GAMT is a missense variant predicted to cause the substitution of a phenylalanine for a leucine at amino acid position 157 (p.Phe157Leu). This variant has been identified in two individuals in the Exome Variant Server database without detailed phenotypic information available (PMID:26003046). The highest population frequency in gnomAD v4.1.0. is 0.00002119 (25/1180010 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in HeLa cells resulted in similar activity versus wild-type GAMT, indicating that this variant does not impact protein function (PMID:26003046) (BS3_Supporting). The computational predictor REVEL gives a score of 0.259 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 517082). Although there is conflicting evidence, with two benign criteria were met (BP4 and BS3_Supporting) and one pathogenic criterion met (PM2_Supporting), the consensus from the ClinGen CCDS VCEP is that this variant is likely benign for GAMT deficiency, based upon the in silico and functional evidence. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BS3_Supporting, BP4 (classification modified to likely benign)(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 14, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA9043635/MONDO:0012999/026

Frequency

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

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:1B:2

Conservation

PhyloP100: 0.855

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.

BS3

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.471T>G	p.Phe157Leu	missense_variant	Exon 5 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3 link	c.471T>G	p.Phe157Leu	missense_variant	Exon 5 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8 link	c.471T>G	p.Phe157Leu	missense_variant	Exon 5 of 6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152180

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

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250792

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461138

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111976

Other (OTH)

AF:

0.0000166

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000131

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

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:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15276

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:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

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: 0.375

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:

0.000125

Hom.:

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cerebral creatine deficiency syndrome

Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine with leucine at codon 157 of the GAMT protein (p.Phe157Leu). The phenylalanine residue is moderately conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs372260609, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 26003046). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Nov 08, 2017

GeneDx

Significance:Likely 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. -

Deficiency of guanidinoacetate methyltransferase

Benign:1

Nov 14, 2024

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.471T>G variant in GAMT is a missense variant predicted to cause the substitution of a phenylalanine for a leucine at amino acid position 157 (p.Phe157Leu). This variant has been identified in two individuals in the Exome Variant Server database without detailed phenotypic information available (PMID: 26003046). The highest population frequency in gnomAD v4.1.0. is 0.00002119 (25/1180010 alleles) in the European (Non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). Expression of the variant in HeLa cells resulted in similar activity versus wild-type GAMT, indicating that this variant does not impact protein function (PMID: 26003046) (BS3_Supporting). The computational predictor REVEL gives a score of 0.259 which is below the threshold of 0.29, evidence that does not predict a damaging effect on GAMT function (BP4). There is a ClinVar entry for this variant (Variation ID: 517082). Although there is conflicting evidence, with two benign criteria met (BP4 and BS3_Supporting) and one pathogenic criterion met (PM2_Supporting), the consensus from the ClinGen CCDS VCEP is that this variant is likely benign for GAMT deficiency, based upon the in silico and functional evidence. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 2.0.0): PM2_Supporting, BS3_Supporting, BP4 (classification modified to likely benign) (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on November 14, 2024) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.19

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.38

T;.;.

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.64

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.75

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.3

M;.;M

PhyloP100

0.85

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.4

N;.;N

REVEL

Benign

0.26

Sift

Benign

0.61

T;.;T

Sift4G

Benign

0.67

T;.;T

Polyphen

0.0

B;.;.

Vest4

0.23

MutPred

0.38

Gain of catalytic residue at F157 (P = 0.0261);.;Gain of catalytic residue at F157 (P = 0.0261);

MVP

0.82

MPC

0.18

ClinPred

0.10

GERP RS

0.54

Varity_R

0.14

gMVP

0.58

Mutation Taster

=52/48

polymorphism

(source)

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