rs150338273

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_000156.6(GAMT):c.227C>T(p.Ser76Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,608,680 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 2 hom. )

Consequence

GAMT
NM_000156.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:10

Conservation

PhyloP100: 6.65

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a helix (size 5) in uniprot entity GAMT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000156.6

BP4

Computational evidence support a benign effect (MetaRNN=0.2776612).

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000525 (764/1456374) while in subpopulation NFE AF= 0.000668 (742/1110366). AF 95% confidence interval is 0.000628. There are 2 homozygotes in gnomad4_exome. There are 401 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6 link	c.227C>T	p.Ser76Leu	missense_variant	Exon 2 of 6	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2
GAMT	NM_138924.3 link	c.227C>T	p.Ser76Leu	missense_variant	Exon 2 of 5		NP_620279.1	Q14353-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAMT	ENST00000252288.8 link	c.227C>T	p.Ser76Leu	missense_variant	Exon 2 of 6	1	NM_000156.6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000447102.8 link	c.227C>T	p.Ser76Leu	missense_variant	Exon 2 of 5	2		ENSP00000403536.2	Q14353-2
GAMT	ENST00000640762.1 link	c.158C>T	p.Ser53Leu	missense_variant	Exon 2 of 6	5		ENSP00000492031.1	A0A1W2PR36

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.000647

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000254

AC:

AN:

239916

Hom.:

AF XY:

0.000230

AC XY:

AN XY:

130322

show subpopulations

Gnomad AFR exome

AF:

0.0000664

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000518

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000525

AC:

764

AN:

1456374

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

401

AN XY:

723976

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000905

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000193

Gnomad4 NFE exome

AF:

0.000668

Gnomad4 OTH exome

AF:

0.000266

GnomAD4 genome

AF:

0.000374

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.000568

Hom.:

Bravo

AF:

0.000298

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000265

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2025	Published functional studies demonstrate that S76L does not damage the protein function (PMID: 26319512); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26003046, 28758966, 26319512) -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Deficiency of guanidinoacetate methyltransferase

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	GAMT NM_000156.5 exon 2 p.Ser76Leu (c.227C>T): This variant has been reported in the literature in 1 individual, but without phenotype information (Mercimek-Mahmutoglu 2016 PMID:26319512). This variant is present in 0.05% (66/123594) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-1399892-G-A). This variant is present in ClinVar (Variation ID:195022). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. Functional studies suggest a benign effect of this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.227C>T (p.S76L) alteration is located in exon 2 (coding exon 2) of the GAMT gene. This alteration results from a C to T substitution at nucleotide position 227, causing the serine (S) at amino acid position 76 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cerebral creatine deficiency syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 76 of the GAMT protein (p.Ser76Leu). This variant is present in population databases (rs150338273, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 195022). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 26319512). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;.

Eigen

Benign

-0.042

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Uncertain

0.38

MutationAssessor

Uncertain

2.8

M;.;M

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.5

D;.;D

REVEL

Uncertain

0.37

Sift

Uncertain

0.014

D;.;D

Sift4G

Uncertain

0.032

D;.;D

Polyphen

0.66

P;.;.

Vest4

0.43

MVP

0.95

MPC

0.14

ClinPred

0.15

GERP RS

3.2

Varity_R

0.21

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over