chr1-51652037-T-C

Variant names:

• chr1-51652037-T-C
• NM_024586.6:c.158T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_024586.6(OSBPL9):​c.158T>C​(p.Leu53Pro) variant causes a missense change. 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: 32)
• Consequence: OSBPL9 NM_024586.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.42
• Publications: 0 publications found

Genes affected

OSBPL9 (HGNC:16386): (oxysterol binding protein like 9) 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. This family member functions as a cholesterol transfer protein that regulates Golgi structure and function. Multiple transcript variants, most of which encode distinct isoforms, have been identified. Related pseudogenes have been identified on chromosomes 3, 11 and 12. [provided by RefSeq, Jul 2010]

OSBPL9 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• multiple congenital anomalies/dysmorphic syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.941

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024586.6. 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
	OSBPL9	NM_024586.6	MANE Select	c.158T>C	p.Leu53Pro	missense	Exon 2 of 24	NP_078862.4
	OSBPL9	NM_001416292.1		c.212T>C	p.Leu71Pro	missense	Exon 4 of 26	NP_001403221.1
	OSBPL9	NM_001416293.1		c.212T>C	p.Leu71Pro	missense	Exon 5 of 27	NP_001403222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OSBPL9	ENST00000428468.6	TSL:1 MANE Select	c.158T>C	p.Leu53Pro	missense	Exon 2 of 24	ENSP00000407168.1	Q96SU4-1
	OSBPL9	ENST00000453295.5	TSL:1	c.112-17397T>C		intron	N/A	ENSP00000413263.1	Q96SU4-7
	OSBPL9	ENST00000930350.1		c.158T>C	p.Leu53Pro	missense	Exon 2 of 24	ENSP00000600409.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

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	1.0
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		4.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.98
Mutation Taster		=44/56	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: chr1-52117709;