rs41292402

Positions:

• chr17-80108422-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000152.5(GAA):​c.1075+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,232 control chromosomes in the GnomAD database, including 217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (10 hom., cov: 33)
  • Exomes 𝑓: 0.016 (207 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.138

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 17-80108422-C-T is Benign according to our data. Variant chr17-80108422-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 92460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80108422-C-T is described in Lovd as [Likely_benign]. Variant chr17-80108422-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0104 (1588/152344) while in subpopulation NFE AF= 0.0166 (1130/68024). AF 95% confidence interval is 0.0158. There are 10 homozygotes in gnomad4. There are 743 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1075+13C>T		intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1075+13C>T		intron_variant		1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1589 AN: 152226 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00922

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.0103 AC: 2589 AN: 250566 Hom.: 20 AF XY: 0.0108 AC XY: 1467 AN XY: 135756

Gnomad AFR exome AF: 0.00235

Gnomad AMR exome AF: 0.00593

Gnomad ASJ exome AF: 0.00887

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00402

Gnomad FIN exome AF: 0.0122

Gnomad NFE exome AF: 0.0160

Gnomad OTH exome AF: 0.00931

GnomAD4 exome AF: 0.0158 AC: 23126 AN: 1460888 Hom.: 207 Cov.: 39 AF XY: 0.0155 AC XY: 11294 AN XY: 726786

Gnomad4 AFR exome AF: 0.00263

Gnomad4 AMR exome AF: 0.00729

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00427

Gnomad4 FIN exome AF: 0.0112

Gnomad4 NFE exome AF: 0.0187

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0104 AC: 1588 AN: 152344 Hom.: 10 Cov.: 33 AF XY: 0.00997 AC XY: 743 AN XY: 74490

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.00915

Gnomad4 ASJ AF: 0.00548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00394

Gnomad4 FIN AF: 0.0137

Gnomad4 NFE AF: 0.0166

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.0115 Hom.: 2

Bravo AF: 0.0103

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 18, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Glycogen storage disease, type II Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.6
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs41292402; hg19: chr17-78082221;