Genetic Variant GAA:c.693-49C>T (chr17-80107508-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000152.5(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
NM_000152.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.377

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.693-49C>T		intron_variant	Intron 3 of 19	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.693-49C>T		intron_variant	Intron 3 of 19	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0879

AC:

13365

AN:

152120

Hom.:

694

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0659

AC XY:

47812

AN XY:

726008

show subpopulations

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.:

AF XY:

0.0873

AC XY:

6494

AN XY:

74420

show subpopulations

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

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease, type II

Benign:1

Jun 10, 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

-0.83

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over