rs17851582

chr19-1397444-G-Achr19-1397444-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000156.6(GAMT):c.626C>T(p.Thr209Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0937 in 1,610,474 control chromosomes in the GnomAD database, including 7,874 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. T209T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.069 (479 hom., cov: 33)
  • Exomes 𝑓: 0.096 (7395 hom.)
• Consequence: GAMT NM_000156.6 missense
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 2.84

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 Benign. Variant got -18 ACMG points.

• PM1: In a domain RMT2 (size 223) in uniprot entity GAMT_HUMAN there are 69 pathogenic changes around while only 17 benign (80%) in NM_000156.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0026440024).
• BP6: Variant 19-1397444-G-A is Benign according to our data. Variant chr19-1397444-G-A is described in ClinVar as [Benign]. Clinvar id is 21068.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr19-1397444-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAMT	NM_000156.6	c.626C>T	p.Thr209Met	missense_variant	6/6	ENST00000252288.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.626C>T	p.Thr209Met	missense_variant	6/6	1	NM_000156.6	P1
GAMT	ENST00000640762.1	c.557C>T	p.Thr186Met	missense_variant	6/6	5
GAMT	ENST00000640164.1	n.459C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10583 AN: 152176 Hom.: 479 Cov.: 33

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0618

Gnomad ASJ AF: 0.0602

Gnomad EAS AF: 0.000768

Gnomad SAS AF: 0.0656

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0670

GnomAD3 exomes AF: 0.0763 AC: 18891 AN: 247438 Hom.: 849 AF XY: 0.0774 AC XY: 10401 AN XY: 134342

Gnomad AFR exome AF: 0.0163

Gnomad AMR exome AF: 0.0784

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0683

Gnomad FIN exome AF: 0.102

Gnomad NFE exome AF: 0.0951

Gnomad OTH exome AF: 0.0840

GnomAD4 exome AF: 0.0962 AC: 140321 AN: 1458180 Hom.: 7395 Cov.: 32 AF XY: 0.0958 AC XY: 69495 AN XY: 725482

Gnomad4 AFR exome AF: 0.0140

Gnomad4 AMR exome AF: 0.0762

Gnomad4 ASJ exome AF: 0.0679

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.0693

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.106

Gnomad4 OTH exome AF: 0.0907

GnomAD4 genome AF: 0.0695 AC: 10579 AN: 152294 Hom.: 479 Cov.: 33 AF XY: 0.0674 AC XY: 5018 AN XY: 74468

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.0617

Gnomad4 ASJ AF: 0.0602

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.0657

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0663

Alfa AF: 0.0882 Hom.: 625

Bravo AF: 0.0640

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.106 AC: 410

ESP6500AA AF: 0.0204 AC: 90

ESP6500EA AF: 0.0972 AC: 836

ExAC AF: 0.0746 AC: 9036

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0913

EpiControl AF: 0.0865

ClinVar

Significance: Benign

Submissions summary: Benign:14 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 24, 2021	- -
Benign, reviewed by expert panel	curation	ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen	Jun 06, 2022	The NM_000156.6:c.626C>T variant in GAMT is a missense variant predicted to result in the substitution of threonine for methionine at amino acid 209 (p.Thr209Met). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.09656 (12354/ 127944 alleles) in the European non-Finnish population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). There are 987 homozygotes in gnomAD v2.1.1. Given that GAMT deficiency has an early onset, this data supports that the variant does not cause the condition (BS2). The computational predictor REVEL gives a score of 0.313 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). It has been previously reported in a large Italian family (PMID: 12468279), where it did not segregate with AGAT deficiency, including being found in the homozygous state in the father, who was asymptomatic and had normal GAMT enzyme activity. It has also been found in presumed cis with the c.160G>C (p.Ala54Pro) variant in a patient with severe GAMT deficiency, as both parents were heterozygous for both the c.160G>C variant and c.626C>T variant and the patient was homozygous for both variants (PMID: 15108290). In this publication (PMID: 15108290), the c.626C>T was classified as a benign polymorphism due to its high frequency in a group of control individuals screened. It is noted in ClinVar (Variation ID: 21068). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 09, 2018	Variant summary: GAMT c.626C>T (p.Thr209Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.076 in 273748 control chromosomes in the gnomAD database, including 972 homozygotes. The observed variant frequency is approximately 70 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAMT causing Guanidinoactetate methyltransferase deficiency phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.626C>T in individuals affected with Guanidinoactetate methyltransferase deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Battini 2002). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both laboratories classified the variant as benign (1x)/likely benign(1x). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2013	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. -

Mitochondrial complex I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 19, 2016

- -

Cerebral creatine deficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.8	N;.
REVEL	Uncertain	0.31
Sift	Benign	0.19	T;.
Sift4G	Uncertain	0.036	D;.
Polyphen		1.0	D;.
Vest4		0.056
ClinPred		0.025	T
GERP RS		5.1
Varity_R		0.20

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

LitVar

Other links and lift over

dbSNP: rs17851582; hg19: chr19-1397443; COSMIC: COSV52041101; COSMIC: COSV52041101;