12-76369265-C-A

Position:

• chr12-76369265-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020841.5(OSBPL8):​c.2277G>T​(p.Gln759His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: OSBPL8 NM_020841.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190

Genes affected

OSBPL8 (HGNC:16396): (oxysterol binding protein like 8) This gene encodes a member of a family of proteins containing an N-terminal pleckstrin homology domain and a highly conserved C-terminal oxysterol-binding protein-like sterol-binding domain. It binds mutliple lipid-containing molecules, including phosphatidylserine, phosphatidylinositol 4-phosphate (PI4P) and oxysterol, and promotes their exchange between the endoplasmic reticulum and the plasma membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

OSBPL8 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSBPL8	NM_020841.5	c.2277G>T	p.Gln759His	missense_variant	21/24	ENST00000261183.8	NP_065892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSBPL8	ENST00000261183.8	c.2277G>T	p.Gln759His	missense_variant	21/24	1	NM_020841.5	ENSP00000261183.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2024

The c.2277G>T (p.Q759H) alteration is located in exon 21 (coding exon 20) of the OSBPL8 gene. This alteration results from a G to T substitution at nucleotide position 2277, causing the glutamine (Q) at amino acid position 759 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.0081	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	.;D;D;.
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.1	.;M;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.95
MutPred		0.49		.;Gain of catalytic residue at E761 (P = 0.0024);.;.;
MVP		0.55
MPC		1.1
ClinPred		1.0	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-76763045;