rs142351862

Variant names:

• chrX-152869048-C-G
• rs142351862
• NM_015922.3:c.1054C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-152869048-C-G
• chrX-152869048-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015922.3(NSDHL):​c.1054C>G​(p.Leu352Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,210,738 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L352L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.34
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08357096).

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.1054C>G	p.Leu352Val	missense	Exon 8 of 8	NP_057006.1	A0A384NPZ7
	NSDHL	NM_001129765.2		c.1054C>G	p.Leu352Val	missense	Exon 9 of 9	NP_001123237.1	Q15738
	NSDHL	NM_001441099.1		c.1054C>G	p.Leu352Val	missense	Exon 10 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.1054C>G	p.Leu352Val	missense	Exon 8 of 8	ENSP00000359297.3	Q15738
	NSDHL	ENST00000915682.1		c.1090C>G	p.Leu364Val	missense	Exon 9 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.1054C>G	p.Leu352Val	missense	Exon 9 of 9	ENSP00000391854.1	Q15738

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112637 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000546 AC: 1 AN: 183245 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098101 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363455

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35203

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: 54141

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

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

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842026

Other (OTH) AF: 0.00 AC: 0 AN: 46092

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112637 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34787

African (AFR) AF: 0.0000322 AC: 1 AN: 31017

American (AMR) AF: 0.00 AC: 0 AN: 10704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6235

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53271

Other (OTH) AF: 0.00 AC: 0 AN: 1514

Alfa AF: 0.00 Hom.: 46

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Child syndrome;C3151781:CK syndrome (2)
-	1	-	Arachnodactyly;C0026267:Mitral valve prolapse;C0036439:Scoliosis;C0221358:Dolichocephaly;C0240635:High palate;C0241240:Tall stature;C0454644:Delayed speech and language development;C1384666:Hearing impairment;C1836047:Long face;C1844820:Joint hypermobility (1)
-	1	-	CK syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.22
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.14	N
PhyloP100		1.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.14
Sift	Benign	0.60	T
Sift4G	Benign	0.78	T
Polyphen		0.0070	B
Vest4		0.025
MutPred		0.32		Gain of phosphorylation at Y349 (P = 0.1186)
MVP		0.35
MPC		0.22
ClinPred		0.027	T
GERP RS		2.4
Varity_R		0.091
gMVP		0.54
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs142351862; hg19: chrX-152037592;