rs55776826

Positions:

• chr19-1399057-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000156.6(GAMT):​c.460-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,613,130 control chromosomes in the GnomAD database, including 17,240 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1612 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15628 hom.)
• Consequence: GAMT NM_000156.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -3.18

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 19-1399057-C-T is Benign according to our data. Variant chr19-1399057-C-T is described in ClinVar as [Benign]. Clinvar id is 21067.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.460-31G>A		intron_variant		ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.460-31G>A		intron_variant			NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.460-31G>A		intron_variant		1	NM_000156.6	ENSP00000252288	P1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21564 AN: 152052 Hom.: 1611 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.128 AC: 32021 AN: 250562 Hom.: 2268 AF XY: 0.130 AC XY: 17620 AN XY: 135754

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.151

Gnomad FIN exome AF: 0.144

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.126

GnomAD4 exome AF: 0.143 AC: 209012 AN: 1460958 Hom.: 15628 Cov.: 35 AF XY: 0.144 AC XY: 104497 AN XY: 726790

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.0145

Gnomad4 SAS exome AF: 0.149

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.142 AC: 21589 AN: 152172 Hom.: 1612 Cov.: 32 AF XY: 0.139 AC XY: 10374 AN XY: 74408

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.102

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.152

Alfa AF: 0.146 Hom.: 323

Bravo AF: 0.139

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of guanidinoacetate methyltransferase Benign:2 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	Dec 04, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 29. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs55776826; hg19: chr19-1399056;