rs121909834

Positions:

• chrX-152869089-C-CT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_015922.3(NSDHL):​c.1098dup​(p.Arg367SerfsTer33) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.89

Genes affected

NSDHL (HGNC:13398): (NAD(P) dependent steroid dehydrogenase-like) The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5' UTR have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0241 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-152869089-C-CT is Pathogenic according to our data. Variant chrX-152869089-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 21266.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.1098dup	p.Arg367SerfsTer33	frameshift_variant	8/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.1098dup	p.Arg367SerfsTer33	frameshift_variant	9/9		NP_001123237.1
NSDHL	XM_011531178.3	c.1098dup	p.Arg367SerfsTer33	frameshift_variant	10/10		XP_011529480.1
NSDHL	XM_017029564.2	c.1146dup	p.Arg383SerfsTer33	frameshift_variant	8/8		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.1098dup	p.Arg367SerfsTer33	frameshift_variant	8/8	1	NM_015922.3	ENSP00000359297	P1
NSDHL	ENST00000440023.5	c.1098dup	p.Arg367SerfsTer33	frameshift_variant	9/9	5		ENSP00000391854	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

CK syndrome Pathogenic:2 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Dec 14, 2021	- -
not provided, no classification provided	clinical testing	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 10, 2010	- -

Computational scores

Source: dbNSFP v4.3

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: rs121909834; hg19: chrX-152037633;