19-1399828-G-T

Variant names:

• chr19-1399828-G-T
• rs765070826
• NM_000156.6:c.292C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000156.6(GAMT):​c.292C>A​(p.Arg98Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,500 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAMT NM_000156.6 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.723
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 19-1399828-G-T is Benign according to our data. Variant chr19-1399828-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2758251.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.723 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.292C>A	p.Arg98Arg	synonymous	Exon 2 of 6	NP_000147.1
	GAMT	NM_138924.3		c.292C>A	p.Arg98Arg	synonymous	Exon 2 of 5	NP_620279.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.292C>A	p.Arg98Arg	synonymous	Exon 2 of 6	ENSP00000252288.1
	GAMT	ENST00000447102.8	TSL:2	c.292C>A	p.Arg98Arg	synonymous	Exon 2 of 5	ENSP00000403536.2
	GAMT	ENST00000640762.1	TSL:5	c.223C>A	p.Arg75Arg	synonymous	Exon 2 of 6	ENSP00000492031.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432500 Hom.: 0 Cov.: 33 AF XY: 0.00000282 AC XY: 2 AN XY: 710144

African (AFR) AF: 0.00 AC: 0 AN: 32892

American (AMR) AF: 0.00 AC: 0 AN: 40724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25518

East Asian (EAS) AF: 0.00 AC: 0 AN: 38222

South Asian (SAS) AF: 0.00 AC: 0 AN: 82292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49634

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1098206

Other (OTH) AF: 0.00 AC: 0 AN: 59280

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebral creatine deficiency syndrome Benign:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.87
PhyloP100		0.72
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs765070826; hg19: chr19-1399827;