rs782181497

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-152868898-T-A
• chrX-152868898-T-C
• chrX-152868898-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_015922.3(NSDHL):​c.904T>A​(p.Tyr302Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,098,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic 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. Y302H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• CK syndrome

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.753

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.904T>A	p.Tyr302Asn	missense_variant	Exon 8 of 8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.904T>A	p.Tyr302Asn	missense_variant	Exon 9 of 9		NP_001123237.1
NSDHL	NM_001441099.1	c.904T>A	p.Tyr302Asn	missense_variant	Exon 10 of 10		NP_001428028.1
NSDHL	XM_017029564.2	c.952T>A	p.Tyr318Asn	missense_variant	Exon 8 of 8		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.904T>A	p.Tyr302Asn	missense_variant	Exon 8 of 8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.904T>A	p.Tyr302Asn	missense_variant	Exon 9 of 9	5		ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098031 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363385

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

American (AMR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 54144

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40526

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841940

Other (OTH) AF: 0.0000217 AC: 1 AN: 46089

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 302 of the NSDHL protein (p.Tyr302Asn). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. 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 tolerated. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Uncertain	0.43	T;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;.
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Uncertain	0.028	D
MutationAssessor	Uncertain	2.2	M;M
PhyloP100		6.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.30	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.98	D;D
Vest4		0.61
MutPred		0.46		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.86
MPC		0.42
ClinPred		0.84	D
GERP RS		4.1
Varity_R		0.30
gMVP		0.95
Mutation Taster		=75/25	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;