rs1800315

Positions:

chr17-80118786-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.2780C>T (p.Thr927Ile) in gnomAD v2.1.1 is 0.1317 in the African population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92482; 2 star review status) with six submitters classifying the variant as benign, and two as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145778/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.042 ( 363 hom., cov: 32)

Exomes 𝑓: 0.010 ( 484 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel B:14

Conservation

PhyloP100: 2.32

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 -8 ACMG points.

BA1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2780C>T	p.Thr927Ile	missense_variant	19/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2780C>T	p.Thr927Ile	missense_variant	19/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes

AF:

0.0423

AC:

6434

AN:

152174

Hom.:

363

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0160

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0511

Gnomad FIN

AF:

0.0117

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00451

Gnomad OTH

AF:

0.0258

GnomAD3 exomes

AF:

0.0188

AC:

4712

AN:

250594

Hom.:

209

AF XY:

0.0183

AC XY:

2481

AN XY:

135606

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.00660

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.000653

Gnomad SAS exome

AF:

0.0514

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.0116

GnomAD4 exome

AF:

0.0103

AC:

15039

AN:

1461080

Hom.:

484

Cov.:

AF XY:

0.0110

AC XY:

7984

AN XY:

726834

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.00751

Gnomad4 ASJ exome

AF:

0.000574

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0482

Gnomad4 FIN exome

AF:

0.0101

Gnomad4 NFE exome

AF:

0.00406

Gnomad4 OTH exome

AF:

0.0151

GnomAD4 genome

AF:

0.0423

AC:

6448

AN:

152292

Hom.:

363

Cov.:

AF XY:

0.0420

AC XY:

3130

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.131

Gnomad4 AMR

AF:

0.0159

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0519

Gnomad4 FIN

AF:

0.0117

Gnomad4 NFE

AF:

0.00451

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0104

Hom.:

Bravo

AF:

0.0447

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00467

AC:

ESP6500AA

AF:

0.132

AC:

582

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.0219

AC:

2661

Asia WGS

AF:

0.0340

AC:

119

AN:

3478

EpiCase

AF:

0.00398

EpiControl

AF:

0.00320

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2015	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. -

Glycogen storage disease, type II

Benign:5

Benign, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jan 23, 2020	The highest continental population minor allele frequency for c.2780C>T (p.Thr927Ile) in gnomAD v2.1.1 is 0.1317 in the African population. This is higher than the ClinGen LSD VCEP's BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92482; 2 star review status) with six submitters classifying the variant as benign, and two as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2020

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

D;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

.;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

0.86

P;P

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

D;D

REVEL

Uncertain

0.48

Sift

Benign

0.040

D;D

Sift4G

Benign

0.086

T;T

Polyphen

0.95

P;P

Vest4

0.050

MPC

0.13

ClinPred

0.024

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.19

gMVP

0.64

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