1-155237596-A-T

Variant names:

• chr1-155237596-A-T
• rs140335079
• NM_000157.4:c.762-18T>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000157.4(GBA1):​c.762-18T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0117 in 1,612,996 control chromosomes in the GnomAD database, including 149 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.0086 (6 hom., cov: 32)
  • Exomes 𝑓: 0.012 (143 hom.)
• Consequence: GBA1 NM_000157.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.775

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 -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 2 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 1-155237596-A-T is Benign according to our data. Variant chr1-155237596-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 198756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-155237596-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00863 (1314/152346) while in subpopulation NFE AF= 0.0133 (906/68034). AF 95% confidence interval is 0.0126. There are 6 homozygotes in gnomad4. There are 636 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GBA1	NM_000157.4	c.762-18T>A		intron_variant	Intron 6 of 10	ENST00000368373.8	NP_000148.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GBA1	ENST00000368373.8	c.762-18T>A		intron_variant	Intron 6 of 10	1	NM_000157.4	ENSP00000357357.3

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1312 AN: 152228 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00270

Gnomad AMI AF: 0.0318

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00730 AC: 1814 AN: 248494 Hom.: 15 AF XY: 0.00739 AC XY: 994 AN XY: 134492

Gnomad AFR exome AF: 0.00257

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.00138

Gnomad FIN exome AF: 0.00441

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00790

GnomAD4 exome AF: 0.0120 AC: 17591 AN: 1460650 Hom.: 143 Cov.: 33 AF XY: 0.0118 AC XY: 8565 AN XY: 726570

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00146

Gnomad4 FIN exome AF: 0.00437

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.00834

GnomAD4 genome AF: 0.00863 AC: 1314 AN: 152346 Hom.: 6 Cov.: 32 AF XY: 0.00854 AC XY: 636 AN XY: 74500

Gnomad4 AFR AF: 0.00269

Gnomad4 AMR AF: 0.0122

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00409 Hom.: 0

Bravo AF: 0.00934

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 20, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

not provided Benign:2

Aug 29, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GBA c.762-18T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 3/5 splice prediction tools predict the creation of a non-canonical splice acceptor site. However, these predictions have yet to be confirmed by functional studies. This variant was found in 882/111976 control chromosomes (5 homozygotes) at a frequency of 0.0078767, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic GBA variant (0.005), suggesting this variant is likely a benign polymorphism. In addition, one clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Jul 13, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gaucher disease type II;C0268251:Gaucher disease type III;C0752347:Lewy body dementia;C1842704:Gaucher disease perinatal lethal;C1856476:Gaucher disease-ophthalmoplegia-cardiovascular calcification syndrome;C1961835:Gaucher disease type I;C3160718:Parkinson disease, late-onset Benign:1

Sep 14, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.1
DANN	Benign	0.63
BranchPoint Hunter		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs140335079; hg19: chr1-155207387;