rs782376691

Variant names:

• chrX-152865840-C-T
• rs782376691
• NM_015922.3:c.565C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_015922.3(NSDHL):​c.565C>T​(p.Pro189Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000146 in 1,098,177 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000015 (0 hom. 3 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.15
• Publications: 0 publications found

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]

NSDHL Gene-Disease associations (from GenCC):

• CHILD syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• CK syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26519465).
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015922.3. 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
	NSDHL	NM_015922.3	MANE Select	c.565C>T	p.Pro189Ser	missense	Exon 6 of 8	NP_057006.1	A0A384NPZ7
	NSDHL	NM_001129765.2		c.565C>T	p.Pro189Ser	missense	Exon 7 of 9	NP_001123237.1	Q15738
	NSDHL	NM_001441099.1		c.565C>T	p.Pro189Ser	missense	Exon 8 of 10	NP_001428028.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.565C>T	p.Pro189Ser	missense	Exon 6 of 8	ENSP00000359297.3	Q15738
	NSDHL	ENST00000915682.1		c.601C>T	p.Pro201Ser	missense	Exon 7 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.565C>T	p.Pro189Ser	missense	Exon 7 of 9	ENSP00000391854.1	Q15738

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD2 exomes AF: 0.0000109 AC: 2 AN: 183424 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1098177 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 3 AN XY: 363533

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.0000166 AC: 14 AN: 842084

Other (OTH) AF: 0.0000434 AC: 2 AN: 46095

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Child syndrome;C3151781:CK syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L
PhyloP100		5.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N
REVEL	Benign	0.29
Sift	Benign	0.33	T
Sift4G	Benign	0.23	T
Polyphen		0.31	B
Vest4		0.43
MutPred		0.38		Gain of ubiquitination at K191 (P = 0.0725)
MVP		0.69
MPC		0.31
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.38
gMVP		0.76
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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

dbSNP: rs782376691; hg19: chrX-152034384;