chr19-1397505-C-T

Variant names:

• chr19-1397505-C-T
• rs2074899
• NM_000156.6:c.571-6G>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.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
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 129130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	NM_000156.6	MANE Select	c.571-6G>A		splice_region intron	N/A	NP_000147.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAMT	ENST00000252288.8	TSL:1 MANE Select	c.571-6G>A		splice_region intron	N/A	ENSP00000252288.1
	GAMT	ENST00000640762.1	TSL:5	c.502-6G>A		splice_region intron	N/A	ENSP00000492031.1
	GAMT	ENST00000640164.1	TSL:2	n.404-6G>A		splice_region intron	N/A

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

GnomAD2 exomes AF: 0.0768 AC: 18498 AN: 240708 AF XY: 0.0735

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 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

African (AFR) AF: 0.0124 AC: 416 AN: 33474

American (AMR) AF: 0.171 AC: 7651 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0266 AC: 694 AN: 26112

East Asian (EAS) AF: 0.248 AC: 9855 AN: 39684

South Asian (SAS) AF: 0.121 AC: 10410 AN: 86226

European-Finnish (FIN) AF: 0.0123 AC: 513 AN: 41614

Middle Eastern (MID) AF: 0.0233 AC: 134 AN: 5762

European-Non Finnish (NFE) AF: 0.0233 AC: 25911 AN: 1111764

Other (OTH) AF: 0.0466 AC: 2809 AN: 60302

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

African (AFR) AF: 0.0174 AC: 724 AN: 41574

American (AMR) AF: 0.146 AC: 2232 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 105 AN: 3464

East Asian (EAS) AF: 0.267 AC: 1380 AN: 5166

South Asian (SAS) AF: 0.132 AC: 637 AN: 4832

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0239 AC: 1625 AN: 68004

Other (OTH) AF: 0.0455 AC: 96 AN: 2112

Alfa AF: 0.0152 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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 26, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 14, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 24, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Deficiency of guanidinoacetate methyltransferase Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Leigh syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mitochondrial complex I deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cerebral creatine deficiency syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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	-0.82
CADD	Benign	0.14
DANN	Benign	0.86
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2074899; hg19: chr19-1397504; COSMIC: COSV52038652; COSMIC: COSV52038652;