NM_000156.6:c.39C>T

Variant names:

• chr19-1401438-G-A
• rs1262796024
• NM_000156.6:c.39C>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. The gene GAMT is included in the ClinGen Criteria Specification Registry.

• 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: Ambry Genetics, Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Specifications for GAMT are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000156.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.39C>T	p.Gly13Gly	synonymous	Exon 1 of 6	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.39C>T	p.Gly13Gly	synonymous	Exon 1 of 5	NP_620279.1	Q14353-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.39C>T	p.Gly13Gly	synonymous	Exon 1 of 6	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.39C>T	p.Gly13Gly	synonymous	Exon 1 of 6	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.39C>T	p.Gly13Gly	synonymous	Exon 1 of 5	ENSP00000403536.2	Q14353-2

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

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Cerebral creatine deficiency syndrome (1)

Computational scores

Source: dbNSFP v4.9

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;