NM_080597.4:c.2303T>C

Variant names:

• chr18-24170442-A-G
• NM_080597.4:c.2303T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_080597.4(OSBPL1A):​c.2303T>C​(p.Leu768Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: OSBPL1A NM_080597.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.32
• Publications: 0 publications found

Genes affected

OSBPL1A (HGNC:16398): (oxysterol binding protein like 1A) 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, although some members contain only the sterol-binding domain. Transcript variants derived from alternative promoter usage and/or alternative splicing exist; they encode different isoforms. [provided by RefSeq, Jul 2008]

RNA5SP452 (HGNC:43352): (RNA, 5S ribosomal pseudogene 452)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080597.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL1A	NM_080597.4	MANE Select	c.2303T>C	p.Leu768Pro	missense	Exon 24 of 28	NP_542164.2
	OSBPL1A	NM_001242508.1		c.1157T>C	p.Leu386Pro	missense	Exon 12 of 16	NP_001229437.1	Q9BXW6-4
	OSBPL1A	NM_018030.4		c.764T>C	p.Leu255Pro	missense	Exon 10 of 14	NP_060500.3	Q9BXW6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL1A	ENST00000319481.8	TSL:1 MANE Select	c.2303T>C	p.Leu768Pro	missense	Exon 24 of 28	ENSP00000320291.3	Q9BXW6-1
	OSBPL1A	ENST00000399443.7	TSL:1	c.764T>C	p.Leu255Pro	missense	Exon 10 of 14	ENSP00000382372.3	Q9BXW6-2
	OSBPL1A	ENST00000880335.1		c.2303T>C	p.Leu768Pro	missense	Exon 24 of 28	ENSP00000550394.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461794 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.070	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		9.3
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.024	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.78		Gain of glycosylation at L768 (P = 0.0253)
MVP		0.70
MPC		2.1
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.91
gMVP		0.89
Mutation Taster		=23/77	disease causing

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

Other links and lift over

hg19: chr18-21750406;