rs104894909

Positions:

• chrX-152858816-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_015922.3(NSDHL):​c.314C>T​(p.Ala105Val) 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: 22)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 7.49

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-152858816-C-T is Pathogenic according to our data. Variant chrX-152858816-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11426.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.314C>T	p.Ala105Val	missense_variant	4/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.314C>T	p.Ala105Val	missense_variant	5/9		NP_001123237.1
NSDHL	XM_017029564.2	c.362C>T	p.Ala121Val	missense_variant	4/8		XP_016885053.1
NSDHL	XM_011531178.3	c.314C>T	p.Ala105Val	missense_variant	6/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.314C>T	p.Ala105Val	missense_variant	4/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.314C>T	p.Ala105Val	missense_variant	5/9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.314C>T	p.Ala105Val	missense_variant	5/8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Child syndrome Pathogenic:1 Other:1

not provided, no classification provided	clinical testing	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 14, 2000	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 11426). This missense change has been observed in individuals with CHILD syndrome (PMID: 10710235, 15689440, 19906044, 25093865, 26459993). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 105 of the NSDHL protein (p.Ala105Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.68	D
BayesDel_noAF	Pathogenic	0.74
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.060	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.97		Loss of disorder (P = 0.1044);Loss of disorder (P = 0.1044);Loss of disorder (P = 0.1044);
MVP		0.99
MPC		0.76
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.96
gMVP		0.98

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: rs104894909; hg19: chrX-152027360; COSMIC: COSV64744774;