rs3746657

chr20-62289334-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_144498.4(OSBPL2):c.1249+4C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,609,824 control chromosomes in the GnomAD database, including 167,728 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13651 hom., cov: 33)
  • Exomes 𝑓: 0.46 (154077 hom.)
• Consequence: OSBPL2 NM_144498.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.003278
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.78

Genes affected

OSBPL2 (HGNC:15761): (oxysterol binding protein like 2) This gene encodes a member of the oxysterol-binding protein (OSBP) family, a group of intracellular lipid receptors. Most members contain an N-terminal pleckstrin homology domain and a highly conserved C-terminal OSBP-like sterol-binding domain, although the encoded protein contains only the sterol-binding domain. In vitro studies have shown that the encoded protein can bind strongly to phosphatic acid and weakly to phosphatidylinositol 3-phosphate, but cannot bind to 25-hydroxycholesterol. The protein associates with the Golgi apparatus. Transcript variants encoding different isoforms have been described. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 20-62289334-C-T is Benign according to our data. Variant chr20-62289334-C-T is described in ClinVar as [Benign]. Clinvar id is 506081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OSBPL2	NM_144498.4	c.1249+4C>T		splice_donor_region_variant, intron_variant		ENST00000313733.9
OSBPL2	NM_001278649.3	c.850-2369C>T		intron_variant
OSBPL2	NM_001363878.2	c.973+4C>T		splice_donor_region_variant, intron_variant
OSBPL2	NM_014835.5	c.1213+4C>T		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OSBPL2	ENST00000313733.9	c.1249+4C>T		splice_donor_region_variant, intron_variant		1	NM_144498.4	P1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63251 AN: 152016 Hom.: 13652 Cov.: 33

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.479

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.436

GnomAD3 exomes AF: 0.457 AC: 111303 AN: 243386 Hom.: 25598 AF XY: 0.458 AC XY: 60266 AN XY: 131526

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.513

Gnomad SAS exome AF: 0.444

Gnomad FIN exome AF: 0.436

Gnomad NFE exome AF: 0.461

Gnomad OTH exome AF: 0.462

GnomAD4 exome AF: 0.458 AC: 667196 AN: 1457690 Hom.: 154077 Cov.: 43 AF XY: 0.458 AC XY: 331764 AN XY: 724678

Gnomad4 AFR exome AF: 0.264

Gnomad4 AMR exome AF: 0.521

Gnomad4 ASJ exome AF: 0.462

Gnomad4 EAS exome AF: 0.536

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.461

Gnomad4 OTH exome AF: 0.451

GnomAD4 genome AF: 0.416 AC: 63281 AN: 152134 Hom.: 13651 Cov.: 33 AF XY: 0.417 AC XY: 31037 AN XY: 74356

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.478

Gnomad4 ASJ AF: 0.463

Gnomad4 EAS AF: 0.524

Gnomad4 SAS AF: 0.453

Gnomad4 FIN AF: 0.428

Gnomad4 NFE AF: 0.470

Gnomad4 OTH AF: 0.440

Alfa AF: 0.449 Hom.: 7675

Bravo AF: 0.415

Asia WGS AF: 0.522 AC: 1816 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	c.1249+4C>T in intron 12 of OSBPL2: This variant is not expected to have clinica l significance because it has been identified in 55.49% (5823/10494) of Latino c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs3746657). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Autosomal dominant nonsyndromic hearing loss 67 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	8.5
Dann	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0033
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: 50

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3746657; hg19: chr20-60864390; COSMIC: COSV58215848; COSMIC: COSV58215848;