rs150338273

Positions:

• chr19-1399893-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1 BP4 BS1_Supporting BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S76P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (2 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 6.65

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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/exons	MANE	UniProt
GAMT	NM_000156.6	c.227C>T	p.Ser76Leu	missense_variant	2/6	ENST00000252288.8
GAMT	NM_138924.3	c.227C>T	p.Ser76Leu	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.227C>T	p.Ser76Leu	missense_variant	2/6	1	NM_000156.6	P1
GAMT	ENST00000447102.8	c.227C>T	p.Ser76Leu	missense_variant	2/5	2
GAMT	ENST00000640762.1	c.158C>T	p.Ser53Leu	missense_variant	2/6	5

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152188 Hom.: 1 Cov.: 32

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: 61 AN: 239916 Hom.: 0 AF XY: 0.000230 AC XY: 30 AN XY: 130322

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.: 2 Cov.: 33 AF XY: 0.000554 AC XY: 401 AN XY: 723976

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: 57 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74476

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.: 0

Bravo AF: 0.000298

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000931 AC: 8

ExAC AF: 0.000265 AC: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Uncertain:4

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, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2020	Reported as a heterozygous variant in a newborn; however, additional clinical information was not provided (Mercimek-Mahmutoglu et al., 2016); Published functional studies demonstrate that S76L does not damage the protein function (Mercimek-Mahmutoglu et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in nearby residues reported in the Human Gene Mutation Database (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 26003046, 25741868, 26319512) -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -

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

Invitae

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	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.;.
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.8	M;.;M
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.39	T
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	T
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

Other links and lift over

dbSNP: rs150338273; hg19: chr19-1399892; COSMIC: COSV52041554; COSMIC: COSV52041554;