rs139850074

Positions:

chr17-80117685-C-T

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.2417C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001189 (42/35310 alleles) in Latino/Admixed American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.435 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). There is a ClinVar entry for this variant (Variation ID: 252467). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815734/MONDO:0009290/010

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:8B:2

Conservation

PhyloP100: 0.491

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 Uncertain_significance. Variant got -1 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2417C>T	p.Thr806Met	missense_variant	17/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2417C>T	p.Thr806Met	missense_variant	17/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000444

AC:

110

AN:

247782

Hom.:

AF XY:

0.000460

AC XY:

AN XY:

134724

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000393

Gnomad FIN exome

AF:

0.0000929

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000304

AC:

444

AN:

1460242

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

726422

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000985

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000348

Gnomad4 FIN exome

AF:

0.0000767

Gnomad4 NFE exome

AF:

0.000301

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000565

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000658

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00320

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000688

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000582

AC:

ExAC

AF:

0.000354

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Benign:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Uncertain:3Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel	Jun 20, 2023	The NM_000152.5: c.2417C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001189 (42/35310 alleles) in Latino/Admixed American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.435 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). There is a ClinVar entry for this variant (Variation ID: 252467). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4. (Classification approved by the ClinGen Lysosomal Diseases VCEP on June 20, 2023). -

not provided

Uncertain:3Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 23, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2023	Reported previously as part of a thesis project of genetic variation identified among healthy Armenian individuals through exome sequencing (Akopyan, 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22253258, 19343043) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 05, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Oct 16, 2015

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.T806M variant (also known as c.2417C>T), located in coding exon 16 of the GAA gene, results from a C to T substitution at nucleotide position 2417. The threonine at codon 806 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

D;D

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.049

LIST_S2

Benign

0.84

.;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.12

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.0

M;M

MutationTaster

Benign

0.93

N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.4

N;N

REVEL

Uncertain

0.43

Sift

Benign

0.062

T;T

Sift4G

Benign

0.098

T;T

Polyphen

0.81

P;P

Vest4

0.20

MVP

0.97

MPC

0.16

ClinPred

0.012

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.086

gMVP

0.46

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