rs1262796024

Variant names:

• chr19-1401438-G-A
• rs1262796024
• NM_000156.6:c.39C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1401438-G-A
• chr19-1401438-G-C
• chr19-1401438-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000156.6(GAMT):​c.39C>T​(p.Gly13Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000238 in 1,260,138 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G13G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: GAMT NM_000156.6 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0100
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6	c.39C>T	p.Gly13Gly	synonymous_variant	Exon 1 of 6	ENST00000252288.8	NP_000147.1
GAMT	NM_138924.3	c.39C>T	p.Gly13Gly	synonymous_variant	Exon 1 of 5		NP_620279.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.39C>T	p.Gly13Gly	synonymous_variant	Exon 1 of 6	1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000447102.8	c.39C>T	p.Gly13Gly	synonymous_variant	Exon 1 of 5	2		ENSP00000403536.2
GAMT	ENST00000640762.1	c.39C>T	p.Gly13Gly	synonymous_variant	Exon 1 of 6	5		ENSP00000492031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000178 AC: 1 AN: 56148 AF XY: 0.0000299

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: 0.0000474

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000238 AC: 3 AN: 1260138 Hom.: 0 Cov.: 31 AF XY: 0.00000324 AC XY: 2 AN XY: 617538

African (AFR) AF: 0.00 AC: 0 AN: 25642

American (AMR) AF: 0.00 AC: 0 AN: 20190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21472

East Asian (EAS) AF: 0.00 AC: 0 AN: 27620

South Asian (SAS) AF: 0.00 AC: 0 AN: 63184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3796

European-Non Finnish (NFE) AF: 0.00000296 AC: 3 AN: 1014890

Other (OTH) AF: 0.00 AC: 0 AN: 51786

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral creatine deficiency syndrome Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 13 of the GAMT mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the GAMT protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with GAMT-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		0.010
PromoterAI		0.22	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1262796024; hg19: chr19-1401437;