rs587784224

Positions:

• chrX-152867611-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_015922.3(NSDHL):​c.727G>A​(p.Val243Met) variant causes a missense change involving the alteration of a 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 9.71

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898
• PP5: Variant X-152867611-G-A is Pathogenic according to our data. Variant chrX-152867611-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.727G>A	p.Val243Met	missense_variant	7/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.727G>A	p.Val243Met	missense_variant	8/9		NP_001123237.1
NSDHL	XM_017029564.2	c.775G>A	p.Val259Met	missense_variant	7/8		XP_016885053.1
NSDHL	XM_011531178.3	c.727G>A	p.Val243Met	missense_variant	9/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.727G>A	p.Val243Met	missense_variant	7/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.727G>A	p.Val243Met	missense_variant	8/9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.727G>A	p.Val243Met	missense_variant	8/8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 243 of the NSDHL protein (p.Val243Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with CHILD syndrome and/or NSDHL-related conditions (PMID: 34787337; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 159453). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2020	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Aug 31, 2017	- -

Child syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D;D;N
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.69		Loss of catalytic residue at V243 (P = 0.0053);Loss of catalytic residue at V243 (P = 0.0053);Loss of catalytic residue at V243 (P = 0.0053);
MVP		0.98
MPC		0.81
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.92

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: rs587784224; hg19: chrX-152036155; COSMIC: COSV64744513;