17-80102109-G-C

Variant names:

• chr17-80102109-G-C
• rs4889961
• ENST00000574376.1:n.328G>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.-33+219G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.746 in 152,654 control chromosomes in the GnomAD database, including 42,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.75 (42568 hom., cov: 32)
  • Exomes 𝑓: 0.80 (180 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.92
• Publications: 7 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=-0.96).
• BP6: Variant 17-80102109-G-C is Benign according to our data. Variant chr17-80102109-G-C is described in ClinVar as [Benign]. Clinvar id is 1237434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.-33+219G>C		intron_variant	Intron 1 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.-33+219G>C		intron_variant	Intron 1 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113274 AN: 151966 Hom.: 42524 Cov.: 32

Gnomad AFR AF: 0.780

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.594

Gnomad ASJ AF: 0.787

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.815

Gnomad FIN AF: 0.809

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.724

GnomAD4 exome AF: 0.802 AC: 457 AN: 570 Hom.: 180 Cov.: 0 AF XY: 0.804 AC XY: 344 AN XY: 428

African (AFR) AF: 0.929 AC: 13 AN: 14

American (AMR) AF: 0.500 AC: 2 AN: 4

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.563 AC: 9 AN: 16

South Asian (SAS) AF: 1.00 AC: 4 AN: 4

European-Finnish (FIN) AF: 0.900 AC: 18 AN: 20

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.801 AC: 386 AN: 482

Other (OTH) AF: 0.821 AC: 23 AN: 28

GnomAD4 genome AF: 0.745 AC: 113367 AN: 152084 Hom.: 42568 Cov.: 32 AF XY: 0.743 AC XY: 55260 AN XY: 74348

African (AFR) AF: 0.780 AC: 32354 AN: 41472

American (AMR) AF: 0.593 AC: 9070 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.787 AC: 2734 AN: 3472

East Asian (EAS) AF: 0.644 AC: 3301 AN: 5128

South Asian (SAS) AF: 0.815 AC: 3936 AN: 4830

European-Finnish (FIN) AF: 0.809 AC: 8567 AN: 10594

Middle Eastern (MID) AF: 0.864 AC: 254 AN: 294

European-Non Finnish (NFE) AF: 0.751 AC: 51037 AN: 67988

Other (OTH) AF: 0.723 AC: 1522 AN: 2106

Alfa AF: 0.749 Hom.: 4985

Bravo AF: 0.731

Asia WGS AF: 0.735 AC: 2560 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.28
DANN	Benign	0.30
PhyloP100		-2.9
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: rs4889961; hg19: chr17-78075908;