X-152868898-T-C

Variant names:

• chrX-152868898-T-C
• rs782181497
• NM_015922.3:c.904T>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_015922.3(NSDHL):​c.904T>C​(p.Tyr302His) variant causes a missense change. The variant allele was found at a frequency of 0.00000826 in 1,210,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y302N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000082 (0 hom. 1 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.54
• Publications: 1 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 -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40502447).

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.904T>C	p.Tyr302His	missense	Exon 8 of 8	NP_057006.1	A0A384NPZ7
	NSDHL	NM_001129765.2		c.904T>C	p.Tyr302His	missense	Exon 9 of 9	NP_001123237.1	Q15738
	NSDHL	NM_001441099.1		c.904T>C	p.Tyr302His	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.904T>C	p.Tyr302His	missense	Exon 8 of 8	ENSP00000359297.3	Q15738
	NSDHL	ENST00000915682.1		c.940T>C	p.Tyr314His	missense	Exon 9 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.904T>C	p.Tyr302His	missense	Exon 9 of 9	ENSP00000391854.1	Q15738

Frequencies

GnomAD3 genomes AF: 0.00000889 AC: 1 AN: 112503 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000323

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: 0.0000218 AC: 4 AN: 183391 AF XY: 0.0000147

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: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000820 AC: 9 AN: 1098031 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363385

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.0000284 AC: 1 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54144

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40526

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

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841940

Other (OTH) AF: 0.00 AC: 0 AN: 46089

GnomAD4 genome AF: 0.00000889 AC: 1 AN: 112503 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34639

African (AFR) AF: 0.0000323 AC: 1 AN: 30921

American (AMR) AF: 0.00 AC: 0 AN: 10683

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2714

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6236

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53280

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

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	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.41	T
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.47
Sift	Benign	0.53	T
Sift4G	Benign	0.51	T
Polyphen		0.99	D
Vest4		0.26
MutPred		0.52		Loss of loop (P = 0.1242)
MVP		0.86
MPC		0.28
ClinPred		0.47	T
GERP RS		4.1
Varity_R		0.20
gMVP		0.90
Mutation Taster		=95/5	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: rs782181497; hg19: chrX-152037442;