rs55776826

Variant names:

• chr19-1399057-C-T
• rs55776826
• NM_000156.6:c.460-31G>A

Variant summary

Our verdict is Benign. The variant received -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 (★★★). The gene GAMT is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.14 (1612 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15628 hom.)
• Consequence: GAMT NM_000156.6 intron
• Clinical Significance: Benign reviewed by expert panel B:6 O:1
• Conservation: PhyloP100: -3.18
• Publications: 8 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: Benign. The variant received -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 VariationId is 21067.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

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.460-31G>A		intron	N/A	NP_000147.1	Q14353-1
	GAMT	NM_138924.3		c.460-31G>A		intron	N/A	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.460-31G>A		intron	N/A	ENSP00000252288.1	Q14353-1
	GAMT	ENST00000902474.1		c.730-31G>A		intron	N/A	ENSP00000572533.1
	GAMT	ENST00000447102.8	TSL:2	c.460-31G>A		intron	N/A	ENSP00000403536.2	Q14353-2

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

GnomAD2 exomes AF: 0.128 AC: 32021 AN: 250562 AF XY: 0.130

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 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

African (AFR) AF: 0.160 AC: 5343 AN: 33478

American (AMR) AF: 0.103 AC: 4618 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2796 AN: 26134

East Asian (EAS) AF: 0.0145 AC: 576 AN: 39700

South Asian (SAS) AF: 0.149 AC: 12877 AN: 86258

European-Finnish (FIN) AF: 0.144 AC: 7585 AN: 52552

Middle Eastern (MID) AF: 0.119 AC: 684 AN: 5768

European-Non Finnish (NFE) AF: 0.149 AC: 166027 AN: 1111964

Other (OTH) AF: 0.141 AC: 8506 AN: 60384

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

African (AFR) AF: 0.159 AC: 6593 AN: 41512

American (AMR) AF: 0.108 AC: 1656 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3472

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5186

South Asian (SAS) AF: 0.145 AC: 700 AN: 4824

European-Finnish (FIN) AF: 0.142 AC: 1509 AN: 10612

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10263 AN: 67962

Other (OTH) AF: 0.152 AC: 321 AN: 2112

Alfa AF: 0.145 Hom.: 555

Bravo AF: 0.139

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of guanidinoacetate methyltransferase (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.17
DANN	Benign	0.90
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55776826; hg19: chr19-1399056;