17-80111068-G-T

Variant names:

• chr17-80111068-G-T
• rs2304842
• NM_000152.5:c.1636+43G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000152.5(GAA):​c.1636+43G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,580,600 control chromosomes in the GnomAD database, including 2,378 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.059 (547 hom., cov: 33)
  • Exomes 𝑓: 0.029 (1831 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.524
• Publications: 3 publications found

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]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-80111068-G-T is Benign according to our data. Variant chr17-80111068-G-T is described in ClinVar as Benign. ClinVar VariationId is 255355.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1636+43G>T		intron_variant	Intron 11 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1636+43G>T		intron_variant	Intron 11 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8974 AN: 152072 Hom.: 546 Cov.: 33

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.0945

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0354

GnomAD2 exomes AF: 0.0496 AC: 11687 AN: 235428 AF XY: 0.0509

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0376

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.0919

Gnomad FIN exome AF: 0.0334

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0315

GnomAD4 exome AF: 0.0293 AC: 41811 AN: 1428410 Hom.: 1831 Cov.: 27 AF XY: 0.0318 AC XY: 22603 AN XY: 711906

African (AFR) AF: 0.144 AC: 4720 AN: 32730

American (AMR) AF: 0.0349 AC: 1522 AN: 43648

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 509 AN: 25836

East Asian (EAS) AF: 0.115 AC: 4479 AN: 39104

South Asian (SAS) AF: 0.134 AC: 11415 AN: 84948

European-Finnish (FIN) AF: 0.0315 AC: 1611 AN: 51138

Middle Eastern (MID) AF: 0.0187 AC: 107 AN: 5732

European-Non Finnish (NFE) AF: 0.0141 AC: 15328 AN: 1086034

Other (OTH) AF: 0.0358 AC: 2120 AN: 59240

GnomAD4 genome AF: 0.0591 AC: 8992 AN: 152190 Hom.: 547 Cov.: 33 AF XY: 0.0605 AC XY: 4505 AN XY: 74408

African (AFR) AF: 0.143 AC: 5940 AN: 41496

American (AMR) AF: 0.0282 AC: 431 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 62 AN: 3468

East Asian (EAS) AF: 0.0943 AC: 487 AN: 5162

South Asian (SAS) AF: 0.147 AC: 711 AN: 4822

European-Finnish (FIN) AF: 0.0329 AC: 349 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 934 AN: 68010

Other (OTH) AF: 0.0360 AC: 76 AN: 2114

Alfa AF: 0.0320 Hom.: 69

Bravo AF: 0.0594

Asia WGS AF: 0.126 AC: 438 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease, type II Benign:1

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.4
DANN	Benign	0.36
PhyloP100		0.52
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304842; hg19: chr17-78084867;