rs141068024

chrX-152867634-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015922.3(NSDHL):c.750G>A(p.Ala250=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000368 in 1,208,103 control chromosomes in the GnomAD database, including 2 homozygotes. There are 127 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., 58 hem., cov: 23)
  • Exomes 𝑓: 0.00021 (2 hom. 69 hem.)
• Consequence: NSDHL NM_015922.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.646

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-152867634-G-A is Benign according to our data. Variant chrX-152867634-G-A is described in ClinVar as [Benign]. Clinvar id is 211752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.646 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00189 (212/112195) while in subpopulation AFR AF= 0.00644 (199/30922). AF 95% confidence interval is 0.0057. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 58 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.750G>A	p.Ala250=	synonymous_variant	7/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.750G>A	p.Ala250=	synonymous_variant	8/9
NSDHL	XM_017029564.2	c.798G>A	p.Ala266=	synonymous_variant	7/8
NSDHL	XM_011531178.3	c.750G>A	p.Ala250=	synonymous_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.750G>A	p.Ala250=	synonymous_variant	7/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.750G>A	p.Ala250=	synonymous_variant	8/9	5		P1
NSDHL	ENST00000432467.1	c.750G>A	p.Ala250=	synonymous_variant	8/8	3

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 212 AN: 112145 Hom.: 0 Cov.: 23 AF XY: 0.00169 AC XY: 58 AN XY: 34311

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000374

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000376

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000113

Gnomad OTH AF: 0.00133

GnomAD3 exomes AF: 0.000525 AC: 96 AN: 183024 Hom.: 0 AF XY: 0.000370 AC XY: 25 AN XY: 67540

Gnomad AFR exome AF: 0.00661

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000315

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.000442

GnomAD4 exome AF: 0.000213 AC: 233 AN: 1095908 Hom.: 2 Cov.: 30 AF XY: 0.000191 AC XY: 69 AN XY: 361284

Gnomad4 AFR exome AF: 0.00626

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000203

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000512

Gnomad4 OTH exome AF: 0.000283

GnomAD4 genome AF: 0.00189 AC: 212 AN: 112195 Hom.: 0 Cov.: 23 AF XY: 0.00169 AC XY: 58 AN XY: 34371

Gnomad4 AFR AF: 0.00644

Gnomad4 AMR AF: 0.000374

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000378

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000113

Gnomad4 OTH AF: 0.00131

Alfa AF: 0.000822 Hom.: 2

Bravo AF: 0.00193

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 18, 2016

- -

NSDHL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.16
Dann	Benign	0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs141068024; hg19: chrX-152036178;