17-80107752-T-C

Variant names:

• chr17-80107752-T-C
• rs2304845
• NM_000152.5:c.858+30T>C

Variant summary

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

The NM_000152.5(GAA):​c.858+30T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.706 in 1,609,190 control chromosomes in the GnomAD database, including 404,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33310 hom., cov: 33)
  • Exomes 𝑓: 0.71 (371270 hom.)
• Consequence: GAA NM_000152.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.40

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=-0.87).
• BP6: Variant 17-80107752-T-C is Benign according to our data. Variant chr17-80107752-T-C is described in ClinVar as [Benign]. Clinvar id is 167111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-80107752-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.73 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.858+30T>C		intron_variant	Intron 4 of 19	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.858+30T>C		intron_variant	Intron 4 of 19	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99265 AN: 151664 Hom.: 33298 Cov.: 33

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.647

Gnomad AMR AF: 0.557

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.538

Gnomad SAS AF: 0.655

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.836

Gnomad NFE AF: 0.735

Gnomad OTH AF: 0.666

GnomAD3 exomes AF: 0.662 AC: 158806 AN: 239982 Hom.: 53709 AF XY: 0.676 AC XY: 88700 AN XY: 131228

Gnomad AFR exome AF: 0.523

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.522

Gnomad SAS exome AF: 0.666

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.732

Gnomad OTH exome AF: 0.719

GnomAD4 exome AF: 0.711 AC: 1036358 AN: 1457410 Hom.: 371270 Cov.: 60 AF XY: 0.712 AC XY: 516033 AN XY: 724850

Gnomad4 AFR exome AF: 0.533

Gnomad4 AMR exome AF: 0.488

Gnomad4 ASJ exome AF: 0.782

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.667

Gnomad4 FIN exome AF: 0.765

Gnomad4 NFE exome AF: 0.730

Gnomad4 OTH exome AF: 0.708

GnomAD4 genome AF: 0.654 AC: 99307 AN: 151780 Hom.: 33310 Cov.: 33 AF XY: 0.652 AC XY: 48372 AN XY: 74194

Gnomad4 AFR AF: 0.530

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.538

Gnomad4 SAS AF: 0.654

Gnomad4 FIN AF: 0.775

Gnomad4 NFE AF: 0.735

Gnomad4 OTH AF: 0.666

Alfa AF: 0.710 Hom.: 7007

Bravo AF: 0.635

Asia WGS AF: 0.582 AC: 2025 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 06, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 30, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GAA c.858+30T>C variant involves the alteration of a intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 176950/267292 control chromosomes (59783 homozygotes) at a frequency of 0.6620101, which indicates this is the major allele (the allele most commonly observed in the general population). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Glycogen storage disease, type II Benign:1

Jul 08, 2021

Genome-Nilou Lab

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	-0.87
CADD	Benign	0.099
DANN	Benign	0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2304845; hg19: chr17-78081551; COSMIC: COSV56408713; COSMIC: COSV56408713;