rs104894904

Positions:

• chrX-152865819-G-A
• chrX-152865819-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015922.3(NSDHL):​c.544G>A​(p.Ala182Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 113,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 24)
• Consequence: NSDHL NM_015922.3 missense, splice_region
• Scores: Splicing: ADA: 0.0008968
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.54

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38112855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	6/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/9		NP_001123237.1
NSDHL	XM_017029564.2	c.592G>A	p.Ala198Thr	missense_variant, splice_region_variant	6/8		XP_016885053.1
NSDHL	XM_011531178.3	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	8/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	6/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.544G>A	p.Ala182Thr	missense_variant, splice_region_variant	7/8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes AF: 0.00000883 AC: 1 AN: 113227 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35365

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000357

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000883 AC: 1 AN: 113227 Hom.: 0 Cov.: 24 AF XY: 0.0000283 AC XY: 1 AN XY: 35365

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000357

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0073	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Uncertain	0.64	D;D;D
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;.;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.73	N;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.65	N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.30	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.10
MutPred		0.63		Loss of stability (P = 0.0885);Loss of stability (P = 0.0885);Loss of stability (P = 0.0885);
MVP		0.94
MPC		0.21
ClinPred		0.067	T
GERP RS		3.0
Varity_R		0.14
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00090
dbscSNV1_RF	Benign	0.13
SpliceAI score (max)		0.090		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: rs104894904; hg19: chrX-152034363;