NM_144498.4:c.1249+4C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

OSBPL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
OSBPL2	NM_144498.4 link	c.1249+4C>T	splice_region_variant, intron_variant	Intron 12 of 13	ENST00000313733.9	NP_653081.1	Q9H1P3-1
OSBPL2	NM_014835.5 link	c.1213+4C>T	splice_region_variant, intron_variant	Intron 12 of 13		NP_055650.1	Q9H1P3-2
OSBPL2	NM_001363878.2 link	c.973+4C>T	splice_region_variant, intron_variant	Intron 13 of 14		NP_001350807.1
OSBPL2	NM_001278649.3 link	c.850-2369C>T	intron_variant	Intron 11 of 12		NP_001265578.1	E7ET92B4DKJ8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSBPL2	ENST00000313733.9 link	c.1249+4C>T		splice_region_variant, intron_variant	Intron 12 of 13	1	NM_144498.4	ENSP00000316649.3		Q9H1P3-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63251

AN:

152016

Hom.:

13652

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.458

AC XY:

331764

AN XY:

724678

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

17825

35650

53474

71299

89124

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15290

30580

45870

61160

76450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.416

AC:

63281

AN:

152134

Hom.:

13651

Cov.:

AF XY:

0.417

AC XY:

31037

AN XY:

74356

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1878

3757

5635

7514

9392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

602

1204

1806

2408

3010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.445

Hom.:

8093

Bravo

AF:

0.415

Asia WGS

AF:

0.522

AC:

1816

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant nonsyndromic hearing loss 67

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: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

-0.80

CADD

Benign

8.5

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over