12-76392646-A-C

Position:

• chr12-76392646-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020841.5(OSBPL8):​c.864T>G​(p.Asp288Glu) 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 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: OSBPL8 NM_020841.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.178

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.068616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSBPL8	NM_020841.5	c.864T>G	p.Asp288Glu	missense_variant	10/24	ENST00000261183.8	NP_065892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSBPL8	ENST00000261183.8	c.864T>G	p.Asp288Glu	missense_variant	10/24	1	NM_020841.5	ENSP00000261183.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.039	.;T;.;.;T;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.74	.;T;T;.;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.069	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.48	.;N;.;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.0	N;N;.;N;N;N
REVEL	Benign	0.045
Sift	Benign	0.30	T;T;.;T;T;T
Sift4G	Benign	0.34	T;T;T;T;.;.
Polyphen		0.0010, 0.0	.;B;.;.;.;B
Vest4		0.076
MutPred		0.36		.;Gain of catalytic residue at L283 (P = 0);.;.;Gain of catalytic residue at L283 (P = 0);.;
MVP		0.24
MPC		0.33
ClinPred		0.13	T
GERP RS		-0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.093

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

LitVar

Other links and lift over

dbSNP: rs1953612844; hg19: chr12-76786426;