19-1397083-G-A

Position:

• chr19-1397083-G-A

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.*276C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0356 in 469,006 control chromosomes in the GnomAD database, including 1,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (1009 hom., cov: 33)
  • Exomes 𝑓: 0.019 (320 hom.)
• Consequence: GAMT NM_000156.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.354

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-1397083-G-A is Benign according to our data. Variant chr19-1397083-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 328344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAMT	NM_000156.6	c.*276C>T		3_prime_UTR_variant	6/6	ENST00000252288.8	NP_000147.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAMT	ENST00000252288	c.*276C>T		3_prime_UTR_variant	6/6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10578 AN: 152114 Hom.: 1010 Cov.: 33

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0423

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0180

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00903

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0193 AC: 6117 AN: 316776 Hom.: 320 Cov.: 3 AF XY: 0.0185 AC XY: 3050 AN XY: 164750

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0336

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.0000915

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00237

Gnomad4 NFE exome AF: 0.0100

Gnomad4 OTH exome AF: 0.0305

GnomAD4 genome AF: 0.0696 AC: 10596 AN: 152230 Hom.: 1009 Cov.: 33 AF XY: 0.0672 AC XY: 5001 AN XY: 74438

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0182

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00901

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0702 Hom.: 171

Bravo AF: 0.0802

Asia WGS AF: 0.0250 AC: 87 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -

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

- -

Deficiency of guanidinoacetate methyltransferase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.6
DANN	Benign	0.59

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs266810; hg19: chr19-1397082;