17-80113332-G-T

Position:

chr17-80113332-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6

The ENST00000302262.8(GAA):c.2155G>T(p.Ala719Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,595,478 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A719E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

GAA
ENST00000302262.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: -1.95

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000302262.8

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.042203188).

BP6

Variant 17-80113332-G-T is Benign according to our data. Variant chr17-80113332-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 286435.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5 linkuse as main transcript	c.2155G>T	p.Ala719Ser	missense_variant	15/20	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.2155G>T	p.Ala719Ser	missense_variant	15/20	1	NM_000152.5	ENSP00000305692	P1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000256

AC:

AN:

218544

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

118158

show subpopulations

Gnomad AFR exome

AF:

0.000221

Gnomad AMR exome

AF:

0.0000626

Gnomad ASJ exome

AF:

0.00108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000273

Gnomad NFE exome

AF:

0.000342

Gnomad OTH exome

AF:

0.000558

GnomAD4 exome

AF:

0.000179

AC:

259

AN:

1443292

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

124

AN XY:

715934

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.000234

Gnomad4 ASJ exome

AF:

0.000546

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000174

Gnomad4 NFE exome

AF:

0.000186

Gnomad4 OTH exome

AF:

0.000235

GnomAD4 genome

AF:

0.000191

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000137

Hom.:

Bravo

AF:

0.000181

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000456

AC:

ESP6500EA

AF:

0.000466

AC:

ExAC

AF:

0.000290

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 03, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	GAA: BP4, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2024	Identified as heterozygous in an individual with autophagic vacuolar myopathy who had reduced GAA enzyme activity and gene expression in muscle; no second variant in GAA was identified by sequencing or deletion/duplication analysis (PMID: 33393119); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22253258, 19343043, 33393119) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 01, 2023	- -

Glycogen storage disease, type II

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 02, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with [disease]. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2.1.1) <0.01 for a recessive condition. 0.000244 (61 heterozygotes, 0 homozygotes). (SP) 0309 – Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2.1.1) p.(Ala719Glu): 0.000149 (37 heterozygotes, 0 homozygotes). p.(Ala719Thr): 0.000244 (7 heterozygotes, 0 homozygotes). p.(Ala719Val): 0.000009 (2 heterozygotes, 0 homozygotes). (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. Conflicting evidence depending on source. It may be located within a catalytic domain, glycosyl hydrolase family 31 (DECIPHER, PMID: 30281819). (I) 0710 – Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. p.(Ala719Glu): ClinVar: VUS x4. p.(Ala719Thr): ClinVar: VUS x2. p.(Ala719Val): ClinVar: VUS x1. At VCGS, p.(Ala719Glu) has also been previously observed once in our HCM patient cohort. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. ClinVar: Conflicting interpretations of pathogenicity: 2x VUS + 1x Likely benign (most recent). PMID: 30281819: computational analysis only by multiple in silico programs predicts this variant has a neutral effect on the protein. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign -
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 22, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 05, 2021

Variant summary: GAA c.2155G>T (p.Ala719Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 218544 control chromosomes (gnomAD v2.1.1). Furthermore, the variant allele was found at a frequency of 0.0001906 in 152186 control chromosomes in the gnomAD v3.1.1 database, including 1 homozygote. These frequencies are not higher than expected for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease), allowing no conclusion about variant significance. c.2155G>T has been reported in the literature as a single heterozygous occurrence (i.e. no other GAA variants identified) in an individual with a limb girdle-like muscular pattern with persistent hyperCKaemia who exhibited reduced GAA muscle activity. The authors concluded that no GAA pathogenic mutations were detected in their study while their data suggested that reduced GAA activity may occur in any condition of impaired autophagy (Napolitano_2021). This report does not provide unequivocal conclusions about association of the variant with Glycogen Storage Disease, Type 2 (Pompe Disease). Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.0020

DANN

Benign

0.49

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.67

.;T

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.042

T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

-0.55

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.25

PROVEAN

Benign

0.60

N;N

REVEL

Benign

0.21

Sift

Benign

0.41

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.0020

B;B

Vest4

0.086

MVP

0.60

MPC

0.10

ClinPred

0.0052

GERP RS

-9.3

Varity_R

0.029

gMVP

0.47

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