X-152846241-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015922.3(NSDHL):c.-43-41C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 725,255 control chromosomes in the GnomAD database, including 16 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0067 (12 hom., 191 hem., cov: 24)
  • Exomes 𝑓: 0.00087 (4 hom. 131 hem.)
• Consequence: NSDHL NM_015922.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0950

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-152846241-C-G is Benign according to our data. Variant chrX-152846241-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1188131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00674 (761/112969) while in subpopulation AFR AF= 0.0228 (708/31118). AF 95% confidence interval is 0.0214. There are 12 homozygotes in gnomad4. There are 191 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 12 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.-43-41C>G		intron_variant		ENST00000370274.8
NSDHL	NM_001129765.2	c.-43-41C>G		intron_variant
NSDHL	XM_011531178.3	c.-43-41C>G		intron_variant
NSDHL	XM_017029564.2	c.6-41C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.-43-41C>G		intron_variant		1	NM_015922.3	P1
NSDHL	ENST00000432467.1	c.-43-41C>G		intron_variant		3
NSDHL	ENST00000440023.5	c.-43-41C>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 759 AN: 112915 Hom.: 12 Cov.: 24 AF XY: 0.00536 AC XY: 188 AN XY: 35089

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00355

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00923

GnomAD4 exome AF: 0.000866 AC: 530 AN: 612286 Hom.: 4 Cov.: 10 AF XY: 0.000686 AC XY: 131 AN XY: 190960

Gnomad4 AFR exome AF: 0.0241

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000225

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000125

Gnomad4 OTH exome AF: 0.00200

GnomAD4 genome AF: 0.00674 AC: 761 AN: 112969 Hom.: 12 Cov.: 24 AF XY: 0.00543 AC XY: 191 AN XY: 35153

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.00354

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00912

Bravo AF: 0.00773

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	2.6
Dann	Benign	0.50

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: rs60548592; hg19: chrX-152014785;