rs140376273

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000152.5(GAA):c.2161G>C(p.Glu721Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,593,596 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.45

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2161G>C	p.Glu721Gln	missense_variant	15/20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 linkuse as main transcript	c.2161G>C	p.Glu721Gln	missense_variant	15/20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

AF:

0.0000985

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000462

AC:

AN:

216402

Hom.:

AF XY:

0.00

AC XY:

AN XY:

116864

show subpopulations

Gnomad AFR exome

AF:

0.0000742

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000555

AC:

AN:

1441372

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714804

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000168

GnomAD4 genome

AF:

0.0000985

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type II

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 24, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 23, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 721 of the GAA protein (p.Glu721Gln). This variant is present in population databases (rs140376273, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with GAA-related conditions. ClinVar contains an entry for this variant (Variation ID: 284866). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GAA protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 25, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

0.0048

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.72

D;D

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.88

.;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.43

T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

1.3

L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.21

Sift

Benign

0.087

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.069

B;B

Vest4

0.12

MVP

0.97

MPC

0.13

ClinPred

0.18

GERP RS

2.6

Varity_R

0.19

gMVP

0.65

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