chr17-80104471-G-A

Variant names:

• chr17-80104471-G-A
• rs368377256
• NM_000152.5:c.-32-84G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000152.5(GAA):​c.-32-84G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00642 in 1,012,690 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0066 (82 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.44
• Publications: 0 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=-0.89).
• BP6: Variant 17-80104471-G-A is Benign according to our data. Variant chr17-80104471-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1196494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00546 (831/152160) while in subpopulation SAS AF = 0.0467 (225/4818). AF 95% confidence interval is 0.0417. There are 6 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.-32-84G>A		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.-32-84G>A		intron_variant	Intron 1 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.00543 AC: 826 AN: 152042 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0458

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00419

Gnomad OTH AF: 0.00672

GnomAD4 exome AF: 0.00659 AC: 5668 AN: 860530 Hom.: 82 AF XY: 0.00791 AC XY: 3413 AN XY: 431236

African (AFR) AF: 0.00399 AC: 82 AN: 20572

American (AMR) AF: 0.00202 AC: 47 AN: 23258

Ashkenazi Jewish (ASJ) AF: 0.000479 AC: 8 AN: 16714

East Asian (EAS) AF: 0.000454 AC: 15 AN: 33044

South Asian (SAS) AF: 0.0431 AC: 2427 AN: 56246

European-Finnish (FIN) AF: 0.0102 AC: 314 AN: 30780

Middle Eastern (MID) AF: 0.00533 AC: 15 AN: 2812

European-Non Finnish (NFE) AF: 0.00388 AC: 2476 AN: 637406

Other (OTH) AF: 0.00715 AC: 284 AN: 39698

GnomAD4 genome AF: 0.00546 AC: 831 AN: 152160 Hom.: 6 Cov.: 32 AF XY: 0.00625 AC XY: 465 AN XY: 74392

African (AFR) AF: 0.00323 AC: 134 AN: 41512

American (AMR) AF: 0.00275 AC: 42 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000774 AC: 4 AN: 5168

South Asian (SAS) AF: 0.0467 AC: 225 AN: 4818

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00419 AC: 285 AN: 67988

Other (OTH) AF: 0.00712 AC: 15 AN: 2106

Alfa AF: 0.00305 Hom.: 0

Bravo AF: 0.00354

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 14, 2018

GeneDx

Significance: Likely 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	-0.89
CADD	Benign	0.0020
DANN	Benign	0.50
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

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: rs368377256; hg19: chr17-78078270;