chr12-76355999-G-T

Position:

• chr12-76355999-G-T

Variant summary

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

The NM_020841.5(OSBPL8):​c.2560C>A​(p.His854Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: OSBPL8 NM_020841.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.14

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]

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=0.11939201).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSBPL8	NM_020841.5	c.2560C>A	p.His854Asn	missense_variant	24/24	ENST00000261183.8	NP_065892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSBPL8	ENST00000261183.8	c.2560C>A	p.His854Asn	missense_variant	24/24	1	NM_020841.5	ENSP00000261183.3
OSBPL8	ENST00000393249.6	c.2434C>A	p.His812Asn	missense_variant	26/26	1		ENSP00000376939.2
OSBPL8	ENST00000611266.4	c.2434C>A	p.His812Asn	missense_variant	24/24	1		ENSP00000478240.1
OSBPL8	ENST00000393250.8	c.2434C>A	p.His812Asn	missense_variant	23/23	5		ENSP00000376940.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1459060 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 20, 2024

The c.2560C>A (p.H854N) alteration is located in exon 24 (coding exon 23) of the OSBPL8 gene. This alteration results from a C to A substitution at nucleotide position 2560, causing the histidine (H) at amino acid position 854 to be replaced by an asparagine (N). 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	Benign	0.077
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	24
DANN	Benign	0.93
DEOGEN2	Benign	0.011	.;T;.;.
Eigen	Benign	-0.042
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	.;D;D;.
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.060	N;N;.;N
REVEL	Benign	0.075
Sift	Benign	0.31	T;T;.;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.026	.;B;.;.
Vest4		0.19
MutPred		0.28		.;Gain of catalytic residue at H854 (P = 0.0025);.;.;
MVP		0.30
MPC		0.45
ClinPred		0.54	D
GERP RS		6.1
Varity_R		0.090
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1951969108; hg19: chr12-76749779;