17-80112112-G-A

Variant names:

• chr17-80112112-G-A
• rs2304840
• NM_000152.5:c.1754+12G>A

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.1754+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0627 in 1,608,178 control chromosomes in the GnomAD database, including 3,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (314 hom., cov: 34)
  • Exomes 𝑓: 0.063 (3023 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.945
• Publications: 6 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=-0.82).
• BP6: Variant 17-80112112-G-A is Benign according to our data. Variant chr17-80112112-G-A is described in ClinVar as Benign. ClinVar VariationId is 92468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0741 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.1754+12G>A		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1754+12G>A		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1754+12G>A		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.1754+12G>A		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1754+12G>A		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1769+12G>A		intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0627 AC: 9542 AN: 152156 Hom.: 312 Cov.: 34

Gnomad AFR AF: 0.0764

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.0366

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0421

Gnomad SAS AF: 0.0615

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0638

Gnomad OTH AF: 0.0535

GnomAD2 exomes AF: 0.0560 AC: 14040 AN: 250846 AF XY: 0.0568

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.0239

Gnomad ASJ exome AF: 0.0373

Gnomad EAS exome AF: 0.0375

Gnomad FIN exome AF: 0.0537

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0566

GnomAD4 exome AF: 0.0626 AC: 91209 AN: 1455904 Hom.: 3023 Cov.: 29 AF XY: 0.0624 AC XY: 45213 AN XY: 724644

African (AFR) AF: 0.0775 AC: 2589 AN: 33386

American (AMR) AF: 0.0264 AC: 1180 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0397 AC: 1037 AN: 26100

East Asian (EAS) AF: 0.0431 AC: 1708 AN: 39666

South Asian (SAS) AF: 0.0633 AC: 5449 AN: 86134

European-Finnish (FIN) AF: 0.0546 AC: 2888 AN: 52896

Middle Eastern (MID) AF: 0.0234 AC: 135 AN: 5760

European-Non Finnish (NFE) AF: 0.0657 AC: 72695 AN: 1107060

Other (OTH) AF: 0.0586 AC: 3528 AN: 60190

GnomAD4 genome AF: 0.0628 AC: 9557 AN: 152274 Hom.: 314 Cov.: 34 AF XY: 0.0609 AC XY: 4531 AN XY: 74454

African (AFR) AF: 0.0764 AC: 3172 AN: 41542

American (AMR) AF: 0.0366 AC: 561 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3470

East Asian (EAS) AF: 0.0422 AC: 218 AN: 5170

South Asian (SAS) AF: 0.0626 AC: 302 AN: 4828

European-Finnish (FIN) AF: 0.0535 AC: 568 AN: 10620

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0638 AC: 4340 AN: 68014

Other (OTH) AF: 0.0549 AC: 116 AN: 2114

Alfa AF: 0.0605 Hom.: 66

Bravo AF: 0.0642

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease, type II (4)
-	-	4	not specified (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.2
DANN	Benign	0.36
PhyloP100		0.94
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: rs2304840; hg19: chr17-78085911;