rs121908300

chr1-155238144-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000157.4(GBA1):c.751T>C(p.Tyr251His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GBA1 NM_000157.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:2
• Conservation: PhyloP100: 8.10

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 helix (size 18) in uniprot entity GBA1_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000157.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.751T>C	p.Tyr251His	missense_variant	6/11	ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.751T>C	p.Tyr251His	missense_variant	6/11	1	NM_000157.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251490 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gaucher disease type I Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 15, 1993

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 28, 2019

- -

Gaucher disease Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 13, 2020

The p.Tyr251His variant in GBA has been reported in 3 individuals with Gaucher disease (PMID: 8432537, 24685312) and has been identified in 0.010% (1/10080) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908300). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant in 3 individuals with Gaucher disease increases the likelihood that the p.Tyr251His variant is pathogenic (VariationID: 4290; PMID: 8432537, 24685312). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PM3, PP3 (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;.;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M;.;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.023	D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.91
MutPred		0.89		Loss of stability (P = 0.0356);Loss of stability (P = 0.0356);.;.;
MVP		0.97
MPC		2.1
ClinPred		0.99	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.79
gMVP		0.97

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: rs121908300; hg19: chr1-155207935;