12-76410611-T-C

Position:

• chr12-76410611-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2 BP4_Strong BS2

The NM_020841.5(OSBPL8):​c.241A>G​(p.Ile81Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,455,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: OSBPL8 NM_020841.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 Likely_benign. Variant got -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048749626).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OSBPL8	NM_020841.5	c.241A>G	p.Ile81Val	missense_variant	5/24	ENST00000261183.8	NP_065892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OSBPL8	ENST00000261183.8	c.241A>G	p.Ile81Val	missense_variant	5/24	1	NM_020841.5	ENSP00000261183.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1455120 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724236

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: 0.00000452

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Dec 01, 2022

The c.241A>G (p.I81V) alteration is located in exon 5 (coding exon 4) of the OSBPL8 gene. This alteration results from a A to G substitution at nucleotide position 241, causing the isoleucine (I) at amino acid position 81 to be replaced by a valine (V). 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	0.061
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.50
DEOGEN2	Benign	0.040	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.98	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.063
MutPred		0.24		Gain of catalytic residue at K27 (P = 0.0022);
MVP		0.37
ClinPred		0.031	T
GERP RS		0.99

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: chr12-76804391;