rs75671029

Positions:

chr1-155235256-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000157.4(GBA1):c.1444G>A(p.Asp482Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000423 in 1,613,852 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 26)

Exomes 𝑓: 0.00025 ( 2 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5O:1

Conservation

PhyloP100: -0.184

Variant links:

Genes affected

GBA1 (HGNC:4177): (glucosylceramidase beta 1) This gene encodes a lysosomal membrane protein that cleaves the beta-glucosidic linkage of glycosylceramide, an intermediate in glycolipid metabolism. Mutations in this gene cause Gaucher disease, a lysosomal storage disease characterized by an accumulation of glucocerebrosides. A related pseudogene is approximately 12 kb downstream of this gene on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2010]

GBA1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000157.4

BP4

Computational evidence support a benign effect (MetaRNN=0.008077592).

BP6

Variant 1-155235256-C-T is Benign according to our data. Variant chr1-155235256-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 4335.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr1-155235256-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00212 (322/152190) while in subpopulation AFR AF= 0.00749 (311/41496). AF 95% confidence interval is 0.00681. There are 2 homozygotes in gnomad4. There are 151 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4 linkuse as main transcript	c.1444G>A	p.Asp482Asn	missense_variant	10/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8 linkuse as main transcript	c.1444G>A	p.Asp482Asn	missense_variant	10/11	1	NM_000157.4	P1	P04062-1

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

321

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00747

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000522

AC:

131

AN:

251124

Hom.:

AF XY:

0.000413

AC XY:

AN XY:

135726

show subpopulations

Gnomad AFR exome

AF:

0.00751

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000247

AC:

361

AN:

1461662

Hom.:

Cov.:

AF XY:

0.000212

AC XY:

154

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00896

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.00212

AC:

322

AN:

152190

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.00749

Gnomad4 AMR

AF:

0.000458

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:

0.00189

Alfa

AF:

0.000385

Hom.:

Bravo

AF:

0.00271

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000692

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	GBA1: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2020	This variant is associated with the following publications: (PMID: 20425034, 21242499, 19502295, 26296077, 25249066, 19286695) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 05, 2022	BS1 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 06, 2020

Variant summary: GBA c.1444G>A (p.Asp482Asn) results in a conservative amino acid change located in the Glycosyl hydrolase family 30, beta sandwich domain (IPR033452) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 253860 control chromosomes, predominantly at a frequency of 0.0075 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in GBA causing Gaucher Disease phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1444G>A has been reported in the literature in individuals affected with Parkinson's disease (e.g. Asselta_2014, Gan-Or_2015, Neumann_2009). These reports however, do not provide unequivocal conclusions about association of the variant with Gaucher Disease. It was reported in the literature that GBA mutations may be a risk factor for Parkinson's disease (e.g. PMIDs: 19502295, 26860875). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign. -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 23, 2022

- -

Gaucher disease

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 14, 2017

- -

Parkinson disease, late-onset

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jul 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

6.4

DANN

Benign

0.81

DEOGEN2

Uncertain

0.61

D;D;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.65

.;T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.0081

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

0.33

N;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.62

N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.56

T;T;T;T

Sift4G

Benign

0.61

T;T;T;T

Polyphen

0.0

B;B;.;.

Vest4

0.11

MVP

0.56

MPC

0.74

ClinPred

0.0011

GERP RS

-1.2

Varity_R

0.11

gMVP

0.62

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