rs1800305

Positions:

• chr17-80109992-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000152.5(GAA):​c.1374C>T​(p.Tyr458=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,613,054 control chromosomes in the GnomAD database, including 4,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (946 hom., cov: 34)
  • Exomes 𝑓: 0.066 (3853 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.31

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-80109992-C-T is Benign according to our data. Variant chr17-80109992-C-T is described in ClinVar as [Benign]. Clinvar id is 92463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80109992-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1374C>T	p.Tyr458=	synonymous_variant	9/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1374C>T	p.Tyr458=	synonymous_variant	9/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.0974 AC: 14825 AN: 152154 Hom.: 945 Cov.: 34

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0969

GnomAD3 exomes AF: 0.0693 AC: 17332 AN: 250176 Hom.: 851 AF XY: 0.0692 AC XY: 9386 AN XY: 135584

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.000817

Gnomad SAS exome AF: 0.0890

Gnomad FIN exome AF: 0.0603

Gnomad NFE exome AF: 0.0652

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0659 AC: 96273 AN: 1460782 Hom.: 3853 Cov.: 32 AF XY: 0.0667 AC XY: 48438 AN XY: 726722

Gnomad4 AFR exome AF: 0.202

Gnomad4 AMR exome AF: 0.0489

Gnomad4 ASJ exome AF: 0.0713

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0863

Gnomad4 FIN exome AF: 0.0622

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0724

GnomAD4 genome AF: 0.0974 AC: 14830 AN: 152272 Hom.: 946 Cov.: 34 AF XY: 0.0962 AC XY: 7162 AN XY: 74460

Gnomad4 AFR AF: 0.190

Gnomad4 AMR AF: 0.0546

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0740

Gnomad4 FIN AF: 0.0632

Gnomad4 NFE AF: 0.0661

Gnomad4 OTH AF: 0.0955

Alfa AF: 0.0834 Hom.: 318

Bravo AF: 0.100

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0689

EpiControl AF: 0.0679

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Glycogen storage disease, type II Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 21, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 27, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2019

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.21
DANN	Benign	0.89

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: rs1800305; hg19: chr17-78083791;