chr17-80109927-A-G

Variant names:

• chr17-80109927-A-G
• rs2278619
• NM_000152.5:c.1327-18A>G

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.1327-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.74 in 1,603,478 control chromosomes in the GnomAD database, including 441,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (39729 hom., cov: 33)
  • Exomes 𝑓: 0.74 (401490 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -4.59
• Publications: 21 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=-0.92).
• BP6: Variant 17-80109927-A-G is Benign according to our data. Variant chr17-80109927-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.79 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.1327-18A>G		intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1327-18A>G		intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1327-18A>G		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.1327-18A>G		intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1327-18A>G		intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1327-18A>G		intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109467 AN: 152052 Hom.: 39711 Cov.: 33

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.652

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.637

Gnomad SAS AF: 0.811

Gnomad FIN AF: 0.810

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.750

Gnomad OTH AF: 0.702

GnomAD2 exomes AF: 0.720 AC: 179518 AN: 249242 AF XY: 0.736

Gnomad AFR exome AF: 0.694

Gnomad AMR exome AF: 0.511

Gnomad ASJ exome AF: 0.803

Gnomad EAS exome AF: 0.622

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.755

Gnomad OTH exome AF: 0.754

GnomAD4 exome AF: 0.742 AC: 1076857 AN: 1451308 Hom.: 401490 Cov.: 28 AF XY: 0.745 AC XY: 538611 AN XY: 722628

African (AFR) AF: 0.697 AC: 23141 AN: 33200

American (AMR) AF: 0.523 AC: 23327 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.805 AC: 20974 AN: 26040

East Asian (EAS) AF: 0.676 AC: 26803 AN: 39628

South Asian (SAS) AF: 0.809 AC: 69518 AN: 85974

European-Finnish (FIN) AF: 0.798 AC: 41993 AN: 52614

Middle Eastern (MID) AF: 0.817 AC: 4697 AN: 5746

European-Non Finnish (NFE) AF: 0.744 AC: 821511 AN: 1103502

Other (OTH) AF: 0.748 AC: 44893 AN: 60006

GnomAD4 genome AF: 0.720 AC: 109528 AN: 152170 Hom.: 39729 Cov.: 33 AF XY: 0.719 AC XY: 53480 AN XY: 74408

African (AFR) AF: 0.692 AC: 28727 AN: 41512

American (AMR) AF: 0.585 AC: 8951 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2752 AN: 3472

East Asian (EAS) AF: 0.637 AC: 3279 AN: 5150

South Asian (SAS) AF: 0.811 AC: 3905 AN: 4816

European-Finnish (FIN) AF: 0.810 AC: 8584 AN: 10604

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.750 AC: 50999 AN: 68010

Other (OTH) AF: 0.702 AC: 1486 AN: 2116

Alfa AF: 0.743 Hom.: 61819

Bravo AF: 0.701

Asia WGS AF: 0.727 AC: 2530 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Glycogen storage disease, type II (4)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0080
DANN	Benign	0.30
PhyloP100		-4.6
Mutation Taster		=12/88	disease causing

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: rs2278619; hg19: chr17-78083726; COSMIC: COSV56408726; COSMIC: COSV56408726;