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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.1636+43G>T		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1636+43G>T		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1636+43G>T		intron	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1636+43G>T		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1636+43G>T		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1651+43G>T		intron	N/A	ENSP00000603465.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glycogen storage disease, type II (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;