rs606231143

Positions:

• chr1-155235203-C-G
• chrNW_003315906.1-40226-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_000157.4(GBA1):​c.1497G>C​(p.Val499=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000754 in 1,610,832 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (0 hom., cov: 25)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: GBA1 NM_000157.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.280

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 Benign. Variant got -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 1-155235203-C-G is Benign according to our data. Variant chr1-155235203-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 93451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155235203-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBA1	NM_000157.4	c.1497G>C	p.Val499=	synonymous_variant	10/11	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.1497G>C	p.Val499=	synonymous_variant	10/11	1	NM_000157.4	ENSP00000357357	P1

Frequencies

GnomAD3 genomes AF: 0.000672 AC: 101 AN: 150362 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000400

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00238

Gnomad SAS AF: 0.00148

Gnomad FIN AF: 0.000573

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000727

Gnomad OTH AF: 0.000974

GnomAD3 exomes AF: 0.000334 AC: 84 AN: 251128 Hom.: 0 AF XY: 0.000376 AC XY: 51 AN XY: 135722

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000762 AC: 1113 AN: 1460352 Hom.: 1 Cov.: 31 AF XY: 0.000841 AC XY: 611 AN XY: 726418

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000493

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00204

Gnomad4 SAS exome AF: 0.00160

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.000690

Gnomad4 OTH exome AF: 0.000928

GnomAD4 genome AF: 0.000678 AC: 102 AN: 150480 Hom.: 0 Cov.: 25 AF XY: 0.000830 AC XY: 61 AN XY: 73458

Gnomad4 AFR AF: 0.000487

Gnomad4 AMR AF: 0.000399

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00239

Gnomad4 SAS AF: 0.00148

Gnomad4 FIN AF: 0.000573

Gnomad4 NFE AF: 0.000727

Gnomad4 OTH AF: 0.000963

Alfa AF: 0.00151 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 21, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 28, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 24, 2012	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2024

GBA1: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	6.1
DANN	Benign	0.76

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: rs1135675; hg19: chr1-155204994;