NM_000157.4:c.1344C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP2

The NM_000157.4(GBA1):​c.1344C>G​(p.Asp448Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D448V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GBA1
NM_000157.4 missense

Scores

5
8
6

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.855

Publications

2 publications found
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 Gene-Disease associations (from GenCC):
  • Parkinson disease
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • Gaucher disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
  • Gaucher disease perinatal lethal
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
  • late-onset Parkinson disease
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
  • Gaucher disease type I
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
  • Gaucher disease type II
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
  • Gaucher disease type III
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
  • Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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 chr1-155235726-T-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 4294.Status of the report is no_assertion_criteria_provided, 0 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 1.1739 (below the threshold of 3.09). Trascript score misZ: 2.2879 (below the threshold of 3.09). GenCC associations: The gene is linked to late-onset Parkinson disease, Gaucher disease perinatal lethal, Gaucher disease, Gaucher disease type I, Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome, Gaucher disease type II, Parkinson disease, Gaucher disease type III.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GBA1NM_000157.4 linkc.1344C>G p.Asp448Glu 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.1344C>G p.Asp448Glu missense_variant Exon 9 of 11 1 NM_000157.4 ENSP00000357357.3 P04062-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD2 exomes
AF:
0.00000400
AC:
1
AN:
250178
AF XY:
0.00000740
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461296
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726866
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44588
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26120
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86118
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53384
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111770
Other (OTH)
AF:
0.00
AC:
0
AN:
60380
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
30
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000595

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.42
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.93
D;D;.;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.23
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.94
.;D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Uncertain
0.72
D;D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.1
M;M;.;.
PhyloP100
0.85
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-2.0
N;N;N;N
REVEL
Pathogenic
0.74
Sift
Benign
0.034
D;D;D;D
Sift4G
Benign
0.062
T;T;T;T
Polyphen
0.21
B;B;.;.
Vest4
0.57
MutPred
0.53
Loss of solvent accessibility (P = 0.0561);Loss of solvent accessibility (P = 0.0561);.;.;
MVP
0.95
MPC
0.72
ClinPred
0.35
T
GERP RS
1.6
Varity_R
0.56
gMVP
0.85
Mutation Taster
=47/53
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs78802049; hg19: chr1-155205516; API