19-1397048-G-C

Position:

• chr19-1397048-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000252288(GAMT):​c.*311C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0397 in 379,452 control chromosomes in the GnomAD database, including 1,257 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 (1006 hom., cov: 33)
  • Exomes 𝑓: 0.020 (251 hom.)
• Consequence: GAMT ENST00000252288 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.941

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=-0.87).
• BP6: Variant 19-1397048-G-C is Benign according to our data. Variant chr19-1397048-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 328343.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.*311C>G		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.*311C>G		3_prime_UTR_variant	6/6	1	NM_000156.6	ENSP00000252288.1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10564 AN: 152072 Hom.: 1007 Cov.: 33

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0422

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0198 AC: 4496 AN: 227262 Hom.: 251 Cov.: 0 AF XY: 0.0191 AC XY: 2263 AN XY: 118776

Gnomad4 AFR exome AF: 0.225

Gnomad4 AMR exome AF: 0.0338

Gnomad4 ASJ exome AF: 0.0280

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.0173

Gnomad4 FIN exome AF: 0.00221

Gnomad4 NFE exome AF: 0.00959

Gnomad4 OTH exome AF: 0.0289

GnomAD4 genome AF: 0.0695 AC: 10582 AN: 152190 Hom.: 1006 Cov.: 33 AF XY: 0.0671 AC XY: 4992 AN XY: 74416

Gnomad4 AFR AF: 0.216

Gnomad4 AMR AF: 0.0422

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0189

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00900

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0118 Hom.: 21

Bravo AF: 0.0803

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

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

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	-0.87
CADD	Benign	1.1
DANN	Benign	0.78

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs266811; hg19: chr19-1397047;