rs78855075

Positions:

• chr17-80107508-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000302262.8(GAA):​c.693-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0672 in 1,611,454 control chromosomes in the GnomAD database, including 4,317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (695 hom., cov: 34)
  • Exomes 𝑓: 0.065 (3622 hom.)
• Consequence: GAA ENST00000302262.8 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.377

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-80107508-C-T is Benign according to our data. Variant chr17-80107508-C-T is described in ClinVar as [Benign]. Clinvar id is 255366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107508-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.693-49C>T		intron_variant		ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.693-49C>T		intron_variant		1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes AF: 0.0879 AC: 13365 AN: 152120 Hom.: 694 Cov.: 34

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.0692

Gnomad AMR AF: 0.0526

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0634

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0914

GnomAD3 exomes AF: 0.0668 AC: 16556 AN: 247886 Hom.: 729 AF XY: 0.0673 AC XY: 9064 AN XY: 134618

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.0439

Gnomad ASJ exome AF: 0.0721

Gnomad EAS exome AF: 0.000439

Gnomad SAS exome AF: 0.0889

Gnomad FIN exome AF: 0.0604

Gnomad NFE exome AF: 0.0653

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0650 AC: 94852 AN: 1459216 Hom.: 3622 Cov.: 32 AF XY: 0.0659 AC XY: 47812 AN XY: 726008

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0469

Gnomad4 ASJ exome AF: 0.0713

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.0864

Gnomad4 FIN exome AF: 0.0625

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0707

GnomAD4 genome AF: 0.0878 AC: 13371 AN: 152238 Hom.: 695 Cov.: 34 AF XY: 0.0873 AC XY: 6494 AN XY: 74420

Gnomad4 AFR AF: 0.156

Gnomad4 AMR AF: 0.0525

Gnomad4 ASJ AF: 0.0709

Gnomad4 EAS AF: 0.000773

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.0634

Gnomad4 NFE AF: 0.0661

Gnomad4 OTH AF: 0.0900

Alfa AF: 0.0816 Hom.: 105

Bravo AF: 0.0900

Asia WGS AF: 0.0410 AC: 143 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Glycogen storage disease, type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.82
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs78855075; hg19: chr17-78081307;