17-80101663-G-C

Variant names:

• chr17-80101663-G-C
• rs2304849
• NM_000152.5:c.-260G>C

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.-260G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 151,788 control chromosomes in the GnomAD database, including 2,727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2727 hom., cov: 32)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: GAA NM_000152.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.528
• Publications: 11 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=-0.8).
• BP6: Variant 17-80101663-G-C is Benign according to our data. Variant chr17-80101663-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 325769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.239 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.-260G>C		5_prime_UTR	Exon 1 of 20	NP_000143.2	P10253
	GAA	NM_001406741.1		c.-170G>C		5_prime_UTR	Exon 1 of 21	NP_001393670.1	P10253
	GAA	NM_001079803.3		c.-113+38G>C		intron	N/A	NP_001073271.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.-260G>C		5_prime_UTR	Exon 1 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.-113+38G>C		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000574376.1	TSL:1	n.29+38G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25639 AN: 151578 Hom.: 2726 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.213

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0545

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.205

Gnomad MID AF: 0.236

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.104 AC: 10 AN: 96 Hom.: 0 Cov.: 0 AF XY: 0.0781 AC XY: 5 AN XY: 64

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.122 AC: 10 AN: 82

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.169 AC: 25629 AN: 151692 Hom.: 2727 Cov.: 32 AF XY: 0.166 AC XY: 12278 AN XY: 74144

African (AFR) AF: 0.0503 AC: 2089 AN: 41498

American (AMR) AF: 0.168 AC: 2563 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 822 AN: 3468

East Asian (EAS) AF: 0.0545 AC: 281 AN: 5160

South Asian (SAS) AF: 0.143 AC: 689 AN: 4826

European-Finnish (FIN) AF: 0.205 AC: 2131 AN: 10406

Middle Eastern (MID) AF: 0.243 AC: 71 AN: 292

European-Non Finnish (NFE) AF: 0.242 AC: 16388 AN: 67764

Other (OTH) AF: 0.190 AC: 401 AN: 2108

Alfa AF: 0.112 Hom.: 193

Bravo AF: 0.163

Asia WGS AF: 0.0850 AC: 295 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.47
PhyloP100		-0.53
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2304849; hg19: chr17-78075462;