rs3746657

Variant names:

• chr20-62289334-C-T
• rs3746657
• NM_144498.4:c.1249+4C>T

Variant summary

Our verdict is Benign. The variant received -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 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. 2/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.003278
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.78
• Publications: 16 publications found

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]

OSBPL2 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 67

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144498.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL2	NM_144498.4	MANE Select	c.1249+4C>T		splice_region intron	N/A	NP_653081.1	Q9H1P3-1
	OSBPL2	NM_014835.5		c.1213+4C>T		splice_region intron	N/A	NP_055650.1	Q9H1P3-2
	OSBPL2	NM_001363878.2		c.973+4C>T		splice_region intron	N/A	NP_001350807.1	A0A2R8YDU7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL2	ENST00000313733.9	TSL:1 MANE Select	c.1249+4C>T		splice_region intron	N/A	ENSP00000316649.3	Q9H1P3-1
	OSBPL2	ENST00000358053.3	TSL:1	c.1213+4C>T		splice_region intron	N/A	ENSP00000350755.2	Q9H1P3-2
	OSBPL2	ENST00000865094.1		c.1393+4C>T		splice_region intron	N/A	ENSP00000535153.1

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

GnomAD2 exomes AF: 0.457 AC: 111303 AN: 243386 AF XY: 0.458

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 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

African (AFR) AF: 0.264 AC: 8835 AN: 33424

American (AMR) AF: 0.521 AC: 22987 AN: 44150

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 12019 AN: 26040

East Asian (EAS) AF: 0.536 AC: 21218 AN: 39600

South Asian (SAS) AF: 0.442 AC: 37849 AN: 85694

European-Finnish (FIN) AF: 0.424 AC: 22483 AN: 53086

Middle Eastern (MID) AF: 0.454 AC: 2607 AN: 5736

European-Non Finnish (NFE) AF: 0.461 AC: 512035 AN: 1109732

Other (OTH) AF: 0.451 AC: 27163 AN: 60228

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

African (AFR) AF: 0.276 AC: 11437 AN: 41508

American (AMR) AF: 0.478 AC: 7312 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1606 AN: 3470

East Asian (EAS) AF: 0.524 AC: 2697 AN: 5150

South Asian (SAS) AF: 0.453 AC: 2181 AN: 4818

European-Finnish (FIN) AF: 0.428 AC: 4525 AN: 10584

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31938 AN: 67992

Other (OTH) AF: 0.440 AC: 932 AN: 2116

Alfa AF: 0.445 Hom.: 8093

Bravo AF: 0.415

Asia WGS AF: 0.522 AC: 1816 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 67 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.5
DANN	Benign	0.51
PhyloP100		-3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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