19-1397213-T-G

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.*146A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0246 in 943,388 control chromosomes in the GnomAD database, including 1,640 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 (993 hom., cov: 33)
  • Exomes 𝑓: 0.016 (647 hom.)
• Consequence: GAMT NM_000156.6 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.87

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=-0.89).
• BP6: Variant 19-1397213-T-G is Benign according to our data. Variant chr19-1397213-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 328346.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	UniProt
GAMT	NM_000156.6	c.*146A>C		3_prime_UTR_variant	6/6	ENST00000252288.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAMT	ENST00000252288.8	c.*146A>C		3_prime_UTR_variant	6/6	1	NM_000156.6	P1

Frequencies

GnomAD3 genomes AF: 0.0695 AC: 10548 AN: 151710 Hom.: 994 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: 0.0188

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0669

Gnomad NFE AF: 0.00904

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0159 AC: 12625 AN: 791564 Hom.: 647 Cov.: 11 AF XY: 0.0153 AC XY: 6159 AN XY: 402176

Gnomad4 AFR exome AF: 0.218

Gnomad4 AMR exome AF: 0.0268

Gnomad4 ASJ exome AF: 0.0265

Gnomad4 EAS exome AF: 0.0000611

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.00233

Gnomad4 NFE exome AF: 0.00844

Gnomad4 OTH exome AF: 0.0280

GnomAD4 genome AF: 0.0696 AC: 10564 AN: 151824 Hom.: 993 Cov.: 33 AF XY: 0.0672 AC XY: 4986 AN XY: 74212

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.0423

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0190

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00903

Gnomad4 OTH AF: 0.0578

Alfa AF: 0.0190 Hom.: 37

Bravo AF: 0.0802

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency Benign:1

Likely 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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

- -

Deficiency of guanidinoacetate methyltransferase Benign:1

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	-0.89
Cadd	Benign	1.6
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs659455; hg19: chr19-1397212;