rs28684874

Variant names:

• chr17-80107730-G-A
• rs5822325
• NM_000152.5:c.858+8G>A

Variant summary

Our verdict is Benign. The variant received -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
• 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: 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 -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 Benign/Likely_benign. ClinVar VariationId is 129122.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 55 AR gene

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.858+8G>A		splice_region intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.858+8G>A		splice_region intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.858+8G>A		splice_region 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.858+8G>A		splice_region intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.858+8G>A		splice_region intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.858+8G>A		splice_region intron	N/A	ENSP00000603465.1

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

GnomAD2 exomes AF: 0.00630 AC: 1371 AN: 217770 AF XY: 0.00501

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 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

African (AFR) AF: 0.000187 AC: 6 AN: 32156

American (AMR) AF: 0.000453 AC: 20 AN: 44174

Ashkenazi Jewish (ASJ) AF: 0.000739 AC: 19 AN: 25724

East Asian (EAS) AF: 0.00465 AC: 183 AN: 39342

South Asian (SAS) AF: 0.000602 AC: 51 AN: 84686

European-Finnish (FIN) AF: 0.000642 AC: 33 AN: 51422

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5690

European-Non Finnish (NFE) AF: 0.000169 AC: 186 AN: 1100008

Other (OTH) AF: 0.000623 AC: 37 AN: 59436

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

African (AFR) AF: 0.000478 AC: 7 AN: 14648

American (AMR) AF: 0.00 AC: 0 AN: 5488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 620

East Asian (EAS) AF: 0.00606 AC: 11 AN: 1814

South Asian (SAS) AF: 0.00405 AC: 5 AN: 1236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1684

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 36

European-Non Finnish (NFE) AF: 0.000524 AC: 7 AN: 13368

Other (OTH) AF: 0.00382 AC: 2 AN: 524

Alfa AF: 0.194 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease, type II (3)
-	-	3	not specified (3)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.1
DANN	Benign	0.33
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs5822325; hg19: chr17-78081529; COSMIC: COSV56407858; COSMIC: COSV56407858;