NM_000152.5:c.858+30T>C

Variant names:

• chr17-80107752-T-C
• rs2304845
• NM_000152.5:c.858+30T>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.858+30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,609,190 control chromosomes in the GnomAD database, including 404,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33310 hom., cov: 33)
  • Exomes 𝑓: 0.71 (371270 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.40
• 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: 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=-0.87).
• BP6: Variant 17-80107752-T-C is Benign according to our data. Variant chr17-80107752-T-C is described in ClinVar as Benign. ClinVar VariationId is 167111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.858+30T>C		intron	N/A	NP_000143.2
	GAA	NM_001079803.3		c.858+30T>C		intron	N/A	NP_001073271.1
	GAA	NM_001079804.3		c.858+30T>C		intron	N/A	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.858+30T>C		intron	N/A	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.858+30T>C		intron	N/A	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.858+30T>C		intron	N/A	ENSP00000460543.2

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99265 AN: 151664 Hom.: 33298 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.836

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.666

GnomAD2 exomes AF: 0.662 AC: 158806 AN: 239982 AF XY: 0.676

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.522

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.711 AC: 1036358 AN: 1457410 Hom.: 371270 Cov.: 60 AF XY: 0.712 AC XY: 516033 AN XY: 724850

African (AFR) AF: 0.533 AC: 17791 AN: 33394

American (AMR) AF: 0.488 AC: 21668 AN: 44382

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20377 AN: 26058

East Asian (EAS) AF: 0.560 AC: 22161 AN: 39578

South Asian (SAS) AF: 0.667 AC: 57399 AN: 86116

European-Finnish (FIN) AF: 0.765 AC: 39657 AN: 51832

Middle Eastern (MID) AF: 0.795 AC: 4566 AN: 5740

European-Non Finnish (NFE) AF: 0.730 AC: 810138 AN: 1110180

Other (OTH) AF: 0.708 AC: 42601 AN: 60130

GnomAD4 genome AF: 0.654 AC: 99307 AN: 151780 Hom.: 33310 Cov.: 33 AF XY: 0.652 AC XY: 48372 AN XY: 74194

African (AFR) AF: 0.530 AC: 21966 AN: 41408

American (AMR) AF: 0.556 AC: 8488 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.769 AC: 2660 AN: 3458

East Asian (EAS) AF: 0.538 AC: 2765 AN: 5140

South Asian (SAS) AF: 0.654 AC: 3148 AN: 4816

European-Finnish (FIN) AF: 0.775 AC: 8204 AN: 10586

Middle Eastern (MID) AF: 0.844 AC: 238 AN: 282

European-Non Finnish (NFE) AF: 0.735 AC: 49849 AN: 67798

Other (OTH) AF: 0.666 AC: 1403 AN: 2108

Alfa AF: 0.704 Hom.: 7101

Bravo AF: 0.635

Asia WGS AF: 0.582 AC: 2025 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Glycogen storage disease, type II (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.099
DANN	Benign	0.21
PhyloP100		-1.4
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)		0.030		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: rs2304845; hg19: chr17-78081551; COSMIC: COSV56408713; COSMIC: COSV56408713;