rs184536370

Positions:

• chrX-152850430-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015922.3(NSDHL):​c.267+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,208,037 control chromosomes in the GnomAD database, including 3 homozygotes. There are 281 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., 41 hem., cov: 23)
  • Exomes 𝑓: 0.00067 (3 hom. 240 hem.)
• Consequence: NSDHL NM_015922.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001858
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.835

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant X-152850430-G-A is Benign according to our data. Variant chrX-152850430-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 211749.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000837 (94/112358) while in subpopulation NFE AF= 0.000957 (51/53282). AF 95% confidence interval is 0.000748. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.267+7G>A		splice_region_variant, intron_variant		ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.267+7G>A		splice_region_variant, intron_variant			NP_001123237.1
NSDHL	XM_011531178.3	c.267+7G>A		splice_region_variant, intron_variant			XP_011529480.1
NSDHL	XM_017029564.2	c.315+7G>A		splice_region_variant, intron_variant			XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.267+7G>A		splice_region_variant, intron_variant		1	NM_015922.3	ENSP00000359297	P1
NSDHL	ENST00000432467.1	c.267+7G>A		splice_region_variant, intron_variant		3		ENSP00000396266
NSDHL	ENST00000440023.5	c.267+7G>A		splice_region_variant, intron_variant		5		ENSP00000391854	P1

Frequencies

GnomAD3 genomes AF: 0.000837 AC: 94 AN: 112303 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 41 AN XY: 34451

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000566

Gnomad ASJ AF: 0.00188

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00506

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000957

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00140 AC: 257 AN: 183209 Hom.: 1 AF XY: 0.00118 AC XY: 80 AN XY: 67693

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000766

Gnomad ASJ exome AF: 0.00241

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00762

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000669 AC: 733 AN: 1095679 Hom.: 3 Cov.: 31 AF XY: 0.000665 AC XY: 240 AN XY: 361075

Gnomad4 AFR exome AF: 0.0000759

Gnomad4 AMR exome AF: 0.000625

Gnomad4 ASJ exome AF: 0.00191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00666

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.000739

GnomAD4 genome AF: 0.000837 AC: 94 AN: 112358 Hom.: 0 Cov.: 23 AF XY: 0.00119 AC XY: 41 AN XY: 34516

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.000566

Gnomad4 ASJ AF: 0.00188

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00506

Gnomad4 NFE AF: 0.000957

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00167 Hom.: 15

Bravo AF: 0.000461

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 28, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.3
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.0
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: rs184536370; hg19: chrX-152018974;