rs77284004

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Moderate

The NM_000157.4(GBA1):​c.1256A>C​(p.Asp419Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D419N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.17
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PS1
Transcript NM_000157.4 (GBA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000157.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-155235814-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1184271.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 1-155235813-T-G is Pathogenic according to our data. Variant chr1-155235813-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3384739.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GBA1NM_000157.4 linkc.1256A>C p.Asp419Ala missense_variant Exon 9 of 11 ENST00000368373.8 NP_000148.2 P04062-1A0A068F658

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GBA1ENST00000368373.8 linkc.1256A>C p.Asp419Ala missense_variant Exon 9 of 11 1 NM_000157.4 ENSP00000357357.3 P04062-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000719
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Gaucher disease Pathogenic:1
Oct 11, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: GBA1 c.1256A>C (p.Asp419Ala) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain (IPR033453) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5e-06 in 1614186 control chromosomes. c.1256A>C has been reported in the literature in the compound heterozygous state in individuals affected with Gaucher Disease (Walley_1993, Saville_2020, Mao_2001, DAmore_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34649574, 11243731, 31707742, 8268935). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.58
D
BayesDel_noAF
Pathogenic
0.60
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;D;.;.
Eigen
Pathogenic
0.75
Eigen_PC
Uncertain
0.61
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H;H;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-7.6
D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
1.0
D;D;.;.
Vest4
0.98
MutPred
0.87
Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);.;.;
MVP
0.91
MPC
2.0
ClinPred
1.0
D
GERP RS
3.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.99
gMVP
0.98

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.

Other links and lift over

dbSNP: rs77284004; hg19: chr1-155205604; API