rs28684874

Positions:

• chr17-80107730-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000152.5(GAA):​c.858+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,482,304 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00037 (55 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002527
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.234

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-80107730-G-A is Benign according to our data. Variant chr17-80107730-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107730-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.858+8G>A		splice_region_variant, intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.858+8G>A		splice_region_variant, intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 32 AN: 39606 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000479

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00604

Gnomad SAS AF: 0.00407

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000524

Gnomad OTH AF: 0.00386

GnomAD3 exomes AF: 0.00630 AC: 1371 AN: 217770 Hom.: 243 AF XY: 0.00501 AC XY: 601 AN XY: 120064

Gnomad AFR exome AF: 0.0183

Gnomad AMR exome AF: 0.00186

Gnomad ASJ exome AF: 0.00405

Gnomad EAS exome AF: 0.00969

Gnomad SAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00196

Gnomad NFE exome AF: 0.00784

Gnomad OTH exome AF: 0.00699

GnomAD4 exome AF: 0.000372 AC: 536 AN: 1442638 Hom.: 55 Cov.: 66 AF XY: 0.000404 AC XY: 290 AN XY: 717258

Gnomad4 AFR exome AF: 0.000187

Gnomad4 AMR exome AF: 0.000453

Gnomad4 ASJ exome AF: 0.000739

Gnomad4 EAS exome AF: 0.00465

Gnomad4 SAS exome AF: 0.000602

Gnomad4 FIN exome AF: 0.000642

Gnomad4 NFE exome AF: 0.000169

Gnomad4 OTH exome AF: 0.000623

GnomAD4 genome AF: 0.000807 AC: 32 AN: 39666 Hom.: 0 Cov.: 0 AF XY: 0.00107 AC XY: 21 AN XY: 19652

Gnomad4 AFR AF: 0.000478

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00606

Gnomad4 SAS AF: 0.00405

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000524

Gnomad4 OTH AF: 0.00382

Alfa AF: 0.194 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 06, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 12, 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	Genetic Services Laboratory, University of Chicago	Mar 13, 2014	- -

Glycogen storage disease, type II Benign:3

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	Jan 30, 2024	- -
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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	GAA: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000025
dbscSNV1_RF	Benign	0.0020
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: rs5822325; hg19: chr17-78081529; COSMIC: COSV56407858; COSMIC: COSV56407858;