rs78855075

Variant names:

• chr17-80107508-C-T
• rs78855075
• NM_000152.5:c.693-49C>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.693-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 1,611,454 control chromosomes in the GnomAD database, including 4,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (695 hom., cov: 34)
  • Exomes 𝑓: 0.065 (3622 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.377
• Publications: 5 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: PanelApp Australia, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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 17-80107508-C-T is Benign according to our data. Variant chr17-80107508-C-T is described in ClinVar as Benign. ClinVar VariationId is 255366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.693-49C>T		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.693-49C>T		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.693-49C>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.693-49C>T		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.693-49C>T		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.693-49C>T		intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13365 AN: 152120 Hom.: 694 Cov.: 34

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0914

GnomAD2 exomes AF: 0.0668 AC: 16556 AN: 247886 AF XY: 0.0673

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.0721

Gnomad EAS exome AF: 0.000439

Gnomad FIN exome AF: 0.0604

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0650 AC: 94852 AN: 1459216 Hom.: 3622 Cov.: 32 AF XY: 0.0659 AC XY: 47812 AN XY: 726008

African (AFR) AF: 0.168 AC: 5605 AN: 33448

American (AMR) AF: 0.0469 AC: 2099 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0713 AC: 1861 AN: 26108

East Asian (EAS) AF: 0.000403 AC: 16 AN: 39686

South Asian (SAS) AF: 0.0864 AC: 7447 AN: 86236

European-Finnish (FIN) AF: 0.0625 AC: 3231 AN: 51732

Middle Eastern (MID) AF: 0.128 AC: 736 AN: 5734

European-Non Finnish (NFE) AF: 0.0626 AC: 69590 AN: 1111232

Other (OTH) AF: 0.0707 AC: 4267 AN: 60328

GnomAD4 genome AF: 0.0878 AC: 13371 AN: 152238 Hom.: 695 Cov.: 34 AF XY: 0.0873 AC XY: 6494 AN XY: 74420

African (AFR) AF: 0.156 AC: 6498 AN: 41528

American (AMR) AF: 0.0525 AC: 803 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.0746 AC: 360 AN: 4826

European-Finnish (FIN) AF: 0.0634 AC: 673 AN: 10616

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4495 AN: 68006

Other (OTH) AF: 0.0900 AC: 190 AN: 2112

Alfa AF: 0.0839 Hom.: 116

Bravo AF: 0.0900

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type II (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.82
DANN	Benign	0.73
PhyloP100		-0.38
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs78855075; hg19: chr17-78081307;