rs141068024

Variant names:

• chrX-152867634-G-A
• rs141068024
• NM_015922.3:c.750G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015922.3(NSDHL):​c.750G>A​(p.Ala250Ala) 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:4
• Conservation: PhyloP100: -0.646
• 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: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 58 XL gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	NM_015922.3	MANE Select	c.750G>A	p.Ala250Ala	synonymous	Exon 7 of 8	NP_057006.1
	NSDHL	NM_001129765.2		c.750G>A	p.Ala250Ala	synonymous	Exon 8 of 9	NP_001123237.1
	NSDHL	NM_001441099.1		c.750G>A	p.Ala250Ala	synonymous	Exon 9 of 10	NP_001428028.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.750G>A	p.Ala250Ala	synonymous	Exon 7 of 8	ENSP00000359297.3
	NSDHL	ENST00000440023.5	TSL:5	c.750G>A	p.Ala250Ala	synonymous	Exon 8 of 9	ENSP00000391854.1
	NSDHL	ENST00000432467.1	TSL:3	c.750G>A	p.Ala250Ala	synonymous	Exon 8 of 8	ENSP00000396266.1

Frequencies

GnomAD3 genomes AF: 0.00189 AC: 212 AN: 112145 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.000525 AC: 96 AN: 183024 AF XY: 0.000370

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 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

African (AFR) AF: 0.00626 AC: 165 AN: 26369

American (AMR) AF: 0.0000284 AC: 1 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.000203 AC: 11 AN: 54082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.0000512 AC: 43 AN: 840050

Other (OTH) AF: 0.000283 AC: 13 AN: 46016

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

African (AFR) AF: 0.00644 AC: 199 AN: 30922

American (AMR) AF: 0.000374 AC: 4 AN: 10697

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3520

South Asian (SAS) AF: 0.000378 AC: 1 AN: 2647

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53161

Other (OTH) AF: 0.00131 AC: 2 AN: 1523

Alfa AF: 0.000822 Hom.: 2

Bravo AF: 0.00193

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	NSDHL-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.16
DANN	Benign	0.49
PhyloP100		-0.65
Mutation Taster		=100/0	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: rs141068024; hg19: chrX-152036178;