1-155235112-G-A

Position:

• chr1-155235112-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000157.4(GBA1):​c.1506-12C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000534 in 1,339,744 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 21)
  • Exomes 𝑓: 0.00053 (5 hom.)
• Consequence: GBA1 NM_000157.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005327
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.20

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 1-155235112-G-A is Benign according to our data. Variant chr1-155235112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1177278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBA1	NM_000157.4	c.1506-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000368373.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBA1	ENST00000368373.8	c.1506-12C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000157.4	P1

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 78 AN: 136054 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.0000282

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000771

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000329

Gnomad OTH AF: 0.00112

GnomAD3 exomes AF: 0.000817 AC: 203 AN: 248526 Hom.: 2 AF XY: 0.000767 AC XY: 103 AN XY: 134374

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.0152

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000348

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.000529 AC: 637 AN: 1203690 Hom.: 5 Cov.: 17 AF XY: 0.000532 AC XY: 323 AN XY: 607120

Gnomad4 AFR exome AF: 0.000106

Gnomad4 AMR exome AF: 0.0000998

Gnomad4 ASJ exome AF: 0.0148

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000194

Gnomad4 NFE exome AF: 0.000244

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000573 AC: 78 AN: 136054 Hom.: 0 Cov.: 21 AF XY: 0.000628 AC XY: 41 AN XY: 65336

Gnomad4 AFR AF: 0.0000282

Gnomad4 AMR AF: 0.0000771

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000329

Gnomad4 OTH AF: 0.00112

Alfa AF: 0.00225 Hom.: 1

Bravo AF: 0.000604

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 28, 2021

Variant summary: GBA c.1506-12C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00082 in 248526 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in GBA causing Gaucher Disease (0.00082 vs 0.005), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1506-12C>T in individuals affected with Gaucher Disease and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.94
DANN	Benign	0.84

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.014
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: rs368832292; hg19: chr1-155204903;