rs104894903

Positions:

• chrX-152850418-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015922.3(NSDHL):​c.262C>T​(p.Arg88Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 2.80

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-152850418-C-T is Pathogenic according to our data. Variant chrX-152850418-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11429.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.262C>T	p.Arg88Ter	stop_gained	3/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.262C>T	p.Arg88Ter	stop_gained	4/9		NP_001123237.1
NSDHL	XM_017029564.2	c.310C>T	p.Arg104Ter	stop_gained	3/8		XP_016885053.1
NSDHL	XM_011531178.3	c.262C>T	p.Arg88Ter	stop_gained	5/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.262C>T	p.Arg88Ter	stop_gained	3/8	1	NM_015922.3	ENSP00000359297	P1
NSDHL	ENST00000440023.5	c.262C>T	p.Arg88Ter	stop_gained	4/9	5		ENSP00000391854	P1
NSDHL	ENST00000432467.1	c.262C>T	p.Arg88Ter	stop_gained	4/8	3		ENSP00000396266

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Child syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2000	- -
not provided, no classification provided	clinical testing	GeneReviews	-	Identified as a mosaic mutated allele in a male with CHILD syndrome. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.61	D
MutationTaster	Benign	1.0	A;A
Vest4		0.83
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs104894903; hg19: chrX-152018962;