1-155235196-G-C

Variant names:

• chr1-155235196-G-C
• rs80356771
• NM_000157.4:c.1504C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_000157.4(GBA1):​c.1504C>G​(p.Arg502Gly) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R502C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 25)
• Consequence: GBA1 NM_000157.4 missense, splice_region
• Scores: Splicing: ADA: 0.4108
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-155235196-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1504C>G	p.Arg502Gly	missense_variant, splice_region_variant	Exon 10 of 11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1504C>G	p.Arg502Gly	missense_variant, splice_region_variant	Exon 10 of 11	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.93	.;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.9	L;L;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Benign	0.061	T;T;T;T
Polyphen		0.098	B;B;.;.
Vest4		0.71
MutPred		0.64		Gain of ubiquitination at K505 (P = 0.0737);Gain of ubiquitination at K505 (P = 0.0737);.;.;
MVP		0.86
MPC		1.3
ClinPred		0.96	D
GERP RS		2.1
Varity_R		0.79
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.41
dbscSNV1_RF	Benign	0.54
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

Other links and lift over

dbSNP: rs80356771; hg19: chr1-155204987;