19-1397505-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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

GAMT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAMT	NM_000156.6 link	c.571-6G>A		splice_region_variant, intron_variant	Intron 5 of 5	ENST00000252288.8	NP_000147.1	Q14353-1V9HWB2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GAMT	ENST00000252288.8 link	c.571-6G>A	splice_region_variant, intron_variant	Intron 5 of 5	1	NM_000156.6	ENSP00000252288.1	Q14353-1
GAMT	ENST00000640762.1 link	c.502-6G>A	splice_region_variant, intron_variant	Intron 5 of 5	5		ENSP00000492031.1	A0A1W2PR36
GAMT	ENST00000640164.1 link	n.404-6G>A	splice_region_variant, intron_variant	Intron 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0455

AC:

6917

AN:

152160

Hom.:

445

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0417

AC XY:

30075

AN XY:

721550

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3108

6216

9324

12432

15540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1258

2516

3774

5032

6290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0455

AC:

6933

AN:

152278

Hom.:

448

Cov.:

AF XY:

0.0501

AC XY:

3731

AN XY:

74458

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0239

AC:

1625

AN:

68004

Other (OTH)

AF:

0.0455

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

303

606

909

1212

1515

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

246

328

410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

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

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.14

(source)

DANN

Benign

0.86

PhyloP100

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over