rs78188205

Positions:

• chr1-155236399-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PS1_Moderate PM2 PP3

The NM_000157.4(GBA1):​c.1070C>A​(p.Ala357Asp) variant causes a missense change. 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 UniProt.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.22

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 Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript NM_000157.4 (GBA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1070C>A	p.Ala357Asp	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.1070C>A	p.Ala357Asp	missense_variant	8/11	1	NM_000157.4	ENSP00000357357	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;D;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.0015
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;D;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	0.66	D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.1	N;N;N;D
REVEL	Pathogenic	0.73
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.52	T;T;T;T
Polyphen		0.25	B;B;.;.
Vest4		0.78
MutPred		0.63		Gain of ubiquitination at K360 (P = 0.0477);Gain of ubiquitination at K360 (P = 0.0477);.;.;
MVP		0.90
MPC		1.3
ClinPred		0.59	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.92

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: rs78188205; hg19: chr1-155206190;