rs1800317

Positions:

• chr17-80119334-G-A
• chr17-80119334-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.*3G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,613,106 control chromosomes in the GnomAD database, including 2,389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (548 hom., cov: 32)
  • Exomes 𝑓: 0.029 (1841 hom.)
• Consequence: GAA NM_000152.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -7.35

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=-0.98).
• BP6: Variant 17-80119334-G-A is Benign according to our data. Variant chr17-80119334-G-A is described in ClinVar as [Benign]. Clinvar id is 92459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80119334-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.*3G>A		3_prime_UTR_variant	20/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.*3G>A		3_prime_UTR_variant	20/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9068 AN: 152064 Hom.: 547 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0278

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.0902

Gnomad SAS AF: 0.151

Gnomad FIN AF: 0.0333

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0354

GnomAD3 exomes AF: 0.0490 AC: 12312 AN: 251086 Hom.: 653 AF XY: 0.0502 AC XY: 6820 AN XY: 135828

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0173

Gnomad EAS exome AF: 0.0897

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0146

Gnomad OTH exome AF: 0.0317

GnomAD4 exome AF: 0.0290 AC: 42332 AN: 1460924 Hom.: 1841 Cov.: 31 AF XY: 0.0315 AC XY: 22891 AN XY: 726830

Gnomad4 AFR exome AF: 0.147

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0175

Gnomad4 EAS exome AF: 0.102

Gnomad4 SAS exome AF: 0.136

Gnomad4 FIN exome AF: 0.0317

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0368

GnomAD4 genome AF: 0.0597 AC: 9086 AN: 152182 Hom.: 548 Cov.: 32 AF XY: 0.0614 AC XY: 4570 AN XY: 74384

Gnomad4 AFR AF: 0.146

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.0158

Gnomad4 EAS AF: 0.0900

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.0333

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0360

Alfa AF: 0.0249 Hom.: 66

Bravo AF: 0.0600

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.0111

EpiControl AF: 0.0119

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	May 17, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Glycogen storage disease, type II Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -
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 specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.85
DANN	Benign	0.50
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: rs1800317; hg19: chr17-78093133; COSMIC: COSV56406706; COSMIC: COSV56406706;