Genetic Variant OSBPL6:p.Pro58Leu (chr2-178324247-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_032523.4(OSBPL6):c.173C>T(p.Pro58Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00355 in 1,573,804 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P58Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0037 ( 64 hom. )

Consequence

OSBPL6
NM_032523.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.53

Publications

5 publications found

Variant links:

Genes affected

OSBPL6 (HGNC:16388): (oxysterol binding protein like 6) 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. Transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

OSBPL6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0038986504).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00234 (356/152320) while in subpopulation SAS AF = 0.0247 (119/4822). AF 95% confidence interval is 0.0211. There are 3 homozygotes in GnomAd4. There are 188 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OSBPL6	NM_032523.4 link	c.173C>T	p.Pro58Leu	missense_variant	Exon 4 of 25	ENST00000190611.9	NP_115912.1	Q9BZF3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OSBPL6	ENST00000190611.9 link	c.173C>T	p.Pro58Leu	missense_variant	Exon 4 of 25	1	NM_032523.4	ENSP00000190611.4		Q9BZF3-1

Frequencies

GnomAD3 genomes

AF:

0.00233

AC:

355

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0242

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00270

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00464

AC:

983

AN:

211822

AF XY:

0.00585

show subpopulations

Gnomad AFR exome

AF:

0.000371

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000180

Gnomad FIN exome

AF:

0.0000519

Gnomad NFE exome

AF:

0.00297

Gnomad OTH exome

AF:

0.00425

GnomAD4 exome

AF:

0.00368

AC:

5231

AN:

1421484

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

3033

AN XY:

703284

show subpopulations

African (AFR)

AF:

0.000485

AC:

AN:

32974

American (AMR)

AF:

0.00118

AC:

AN:

42548

Ashkenazi Jewish (ASJ)

AF:

0.000119

AC:

AN:

25282

East Asian (EAS)

AF:

0.0000773

AC:

AN:

38814

South Asian (SAS)

AF:

0.0243

AC:

1979

AN:

81284

European-Finnish (FIN)

AF:

0.0000587

AC:

AN:

51122

Middle Eastern (MID)

AF:

0.00968

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00268

AC:

2907

AN:

1085298

Other (OTH)

AF:

0.00368

AC:

215

AN:

58482

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

213

426

638

851

1064

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00234

AC:

356

AN:

152320

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

188

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41562

American (AMR)

AF:

0.00124

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0247

AC:

119

AN:

4822

European-Finnish (FIN)

AF:

0.000282

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00270

AC:

184

AN:

68024

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00263

Hom.:

Bravo

AF:

0.00179

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00279

AC:

ExAC

AF:

0.00461

AC:

551

Asia WGS

AF:

0.00982

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.013

.;.;.;.;T;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

0.089

FATHMM_MKL

Benign

0.56

LIST_S2

Uncertain

0.96

D;D;D;D;D;.;D

MetaRNN

Benign

0.0039

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N;N;N;N;N;.

PhyloP100

1.5

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.1

N;N;N;N;N;N;N

REVEL

Benign

0.025

Sift

Uncertain

0.022

D;D;D;D;D;D;D

Sift4G

Benign

0.18

T;T;T;T;T;T;T

Polyphen

0.065

B;B;.;B;B;B;B

Vest4

0.30

MVP

0.068

MPC

0.34

ClinPred

0.0077

GERP RS

5.0

Varity_R

0.071

gMVP

0.27

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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2-178324247-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over