chrX-152865840-C-T

Position:

• chrX-152865840-C-T

Variant summary

Our verdict is Likely benign. Variant got -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. 13/20 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:2
• Conservation: PhyloP100: 5.15

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_benign. Variant got -5 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.565C>T	p.Pro189Ser	missense_variant	6/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.565C>T	p.Pro189Ser	missense_variant	7/9		NP_001123237.1
NSDHL	XM_017029564.2	c.613C>T	p.Pro205Ser	missense_variant	6/8		XP_016885053.1
NSDHL	XM_011531178.3	c.565C>T	p.Pro189Ser	missense_variant	8/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.565C>T	p.Pro189Ser	missense_variant	6/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.565C>T	p.Pro189Ser	missense_variant	7/9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.565C>T	p.Pro189Ser	missense_variant	7/8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000109 AC: 2 AN: 183424 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 67862

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome Cov.: 25

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 23, 2015

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 27, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 436069). This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. This variant is present in population databases (rs782376691, gnomAD 0.002%), including at least one homozygous and/or hemizygous individual. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 189 of the NSDHL protein (p.Pro189Ser). -

Computational scores

Source: dbNSFP v4.3

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;D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.7	L;L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.96	N;N;N
REVEL	Benign	0.29
Sift	Benign	0.33	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.31	B;B;.
Vest4		0.43
MutPred		0.38		Gain of ubiquitination at K191 (P = 0.0725);Gain of ubiquitination at K191 (P = 0.0725);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs782376691; hg19: chrX-152034384;