rs75528494

chr1-155236254-G-Cchr1-155236254-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS1 PM1 PM2 PM5 PP3_Strong

The NM_000157.4(GBA1):c.1215C>G(p.Ser405Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S405N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.73

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 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 ClinVar as 2503945
• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 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 chr1-155236255-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1799687.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1215C>G	p.Ser405Arg	missense_variant	8/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1215C>G	p.Ser405Arg	missense_variant	8/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	0.75	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0080	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.88
MutPred		0.67		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);.;.;
MVP		0.96
MPC		1.6
ClinPred		0.96	D
GERP RS		2.6
Varity_R		0.91
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

Other links and lift over

dbSNP: rs75528494; hg19: chr1-155206045;