chr19-1397505-C-T

Position:

• chr19-1397505-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.571-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0408 in 1,601,914 control chromosomes in the GnomAD database, including 3,667 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (448 hom., cov: 33)
  • Exomes 𝑓: 0.040 (3219 hom.)
• Consequence: GAMT NM_000156.6 splice_region, intron
• Scores: Splicing: ADA: 0.00005159
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.107

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-1397505-C-T is Benign according to our data. Variant chr19-1397505-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1397505-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.571-6G>A		splice_region_variant, intron_variant		ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288.8	c.571-6G>A		splice_region_variant, intron_variant		1	NM_000156.6	ENSP00000252288.1
GAMT	ENST00000640762.1	c.502-6G>A		splice_region_variant, intron_variant		5		ENSP00000492031.1
GAMT	ENST00000640164.1	n.404-6G>A		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6917 AN: 152160 Hom.: 445 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.132

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0768 AC: 18498 AN: 240708 Hom.: 1576 AF XY: 0.0735 AC XY: 9646 AN XY: 131280

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.0270

Gnomad EAS exome AF: 0.270

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0125

Gnomad NFE exome AF: 0.0245

Gnomad OTH exome AF: 0.0516

GnomAD4 exome AF: 0.0403 AC: 58393 AN: 1449636 Hom.: 3219 Cov.: 32 AF XY: 0.0417 AC XY: 30075 AN XY: 721550

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0266

Gnomad4 EAS exome AF: 0.248

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0233

Gnomad4 OTH exome AF: 0.0466

GnomAD4 genome AF: 0.0455 AC: 6933 AN: 152278 Hom.: 448 Cov.: 33 AF XY: 0.0501 AC XY: 3731 AN XY: 74458

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.146

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0239

Gnomad4 OTH AF: 0.0455

Alfa AF: 0.0148 Hom.: 6

Bravo AF: 0.0510

Asia WGS AF: 0.210 AC: 731 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0209

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2013	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 26, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -

Deficiency of guanidinoacetate methyltransferase Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Leigh syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Mitochondrial complex I deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cerebral creatine deficiency syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.14
DANN	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000052
dbscSNV1_RF	Benign	0.012
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: rs2074899; hg19: chr19-1397504; COSMIC: COSV52038652; COSMIC: COSV52038652;