chr1-155236295-G-C

Position:

• chr1-155236295-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The ENST00000368373.8(GBA1):​c.1174C>G​(p.Arg392Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R392W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GBA1 ENST00000368373.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.22

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 ENST00000368373.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155236295-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 813336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.774
• PP5: Variant 1-155236295-G-C is Pathogenic according to our data. Variant chr1-155236295-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 4323.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1174C>G	p.Arg392Gly	missense_variant	8/11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1174C>G	p.Arg392Gly	missense_variant	8/11	1	NM_000157.4	ENSP00000357357	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Gaucher disease type III Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;.;.
Eigen	Benign	-0.042
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.59	D
LIST_S2	Uncertain	0.94	.;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	0.98	A;A;A;A;A
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Pathogenic	0.79
Sift	Benign	0.067	T;T;T;T
Sift4G	Benign	0.39	T;T;T;T
Polyphen		0.85	P;P;.;.
Vest4		0.76
MutPred		0.57		Loss of MoRF binding (P = 0.0268);Loss of MoRF binding (P = 0.0268);.;.;
MVP		0.90
MPC		1.3
ClinPred		0.73	D
GERP RS		3.7
Varity_R		0.73
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs121908308; hg19: chr1-155206086;