17-80105844-C-T

Position:

• chr17-80105844-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.642C>T​(p.Ser214Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,608,148 control chromosomes in the GnomAD database, including 35,416 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2499 hom., cov: 34)
  • Exomes 𝑓: 0.21 (32917 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -3.21

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=-0.69).
• BP6: Variant 17-80105844-C-T is Benign according to our data. Variant chr17-80105844-C-T is described in ClinVar as [Benign]. Clinvar id is 92487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80105844-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.21 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.642C>T	p.Ser214Ser	synonymous_variant	3/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.642C>T	p.Ser214Ser	synonymous_variant	3/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25227 AN: 152116 Hom.: 2502 Cov.: 34

Gnomad AFR AF: 0.0740

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.172

GnomAD3 exomes AF: 0.178 AC: 43932 AN: 246290 Hom.: 4794 AF XY: 0.187 AC XY: 24966 AN XY: 133864

Gnomad AFR exome AF: 0.0722

Gnomad AMR exome AF: 0.0997

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.171

Gnomad FIN exome AF: 0.242

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.206 AC: 299792 AN: 1455914 Hom.: 32917 Cov.: 56 AF XY: 0.206 AC XY: 149517 AN XY: 724492

Gnomad4 AFR exome AF: 0.0714

Gnomad4 AMR exome AF: 0.105

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.000554

Gnomad4 SAS exome AF: 0.174

Gnomad4 FIN exome AF: 0.245

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.199

GnomAD4 genome AF: 0.166 AC: 25225 AN: 152234 Hom.: 2499 Cov.: 34 AF XY: 0.165 AC XY: 12318 AN XY: 74432

Gnomad4 AFR AF: 0.0741

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.165

Gnomad4 FIN AF: 0.249

Gnomad4 NFE AF: 0.221

Gnomad4 OTH AF: 0.171

Alfa AF: 0.180 Hom.: 1058

Bravo AF: 0.154

Asia WGS AF: 0.0710 AC: 250 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 12, 2015	- -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Glycogen storage disease, type II Benign:6

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 08, 2016	Variant summary: This GAA c.642C>T variant affects a non-conserved nucleotide, resulting in no amino acid change. 5/5 splice-site tools via Alamut predict that this variant does not affect normal splicing. This variant was found in 21664/120192 control chromosomes from ExAC at a frequency of 0.1802449, which is more than 42 times greater than the maximal expected frequency of a pathogenic allele (0.0042205) in this gene, suggesting this variant is benign. The variant has been cited in at least one adult glycogen storage disease type II patient with an alternative genetic explanation for their disease. In addition, multiple clinical laboratories have classified this variant as benign. Taken together, this variant has been classified as Benign. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 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	-0.69
CADD	Benign	0.40
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1800301; hg19: chr17-78079643; COSMIC: COSV56407138; COSMIC: COSV56407138;