X-152850236-T-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.109-29T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00096 in 1,204,742 control chromosomes in the GnomAD database, including 12 homozygotes. There are 275 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 0.0051 (3 hom., 146 hem., cov: 24)
  • Exomes 𝑓: 0.00054 (9 hom. 129 hem.)
• Consequence: NSDHL NM_015922.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0590

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=-0.84).
• BP6: Variant X-152850236-T-G is Benign according to our data. Variant chrX-152850236-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 1191540.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00505 (568/112376) while in subpopulation AFR AF= 0.017 (527/30951). AF 95% confidence interval is 0.0158. There are 3 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.109-29T>G		intron_variant		ENST00000370274.8
NSDHL	NM_001129765.2	c.109-29T>G		intron_variant
NSDHL	XM_011531178.3	c.109-29T>G		intron_variant
NSDHL	XM_017029564.2	c.157-29T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.109-29T>G		intron_variant		1	NM_015922.3	P1
NSDHL	ENST00000432467.1	c.109-29T>G		intron_variant		3
NSDHL	ENST00000440023.5	c.109-29T>G		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 568 AN: 112325 Hom.: 3 Cov.: 24 AF XY: 0.00423 AC XY: 146 AN XY: 34483

Gnomad AFR AF: 0.0171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00274

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00599

GnomAD3 exomes AF: 0.00147 AC: 270 AN: 183372 Hom.: 0 AF XY: 0.000796 AC XY: 54 AN XY: 67828

Gnomad AFR exome AF: 0.0179

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000883

GnomAD4 exome AF: 0.000539 AC: 589 AN: 1092366 Hom.: 9 Cov.: 28 AF XY: 0.000360 AC XY: 129 AN XY: 358172

Gnomad4 AFR exome AF: 0.0200

Gnomad4 AMR exome AF: 0.00108

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000358

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.00505 AC: 568 AN: 112376 Hom.: 3 Cov.: 24 AF XY: 0.00423 AC XY: 146 AN XY: 34544

Gnomad4 AFR AF: 0.0170

Gnomad4 AMR AF: 0.00273

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00591

Alfa AF: 0.00273 Hom.: 12

Bravo AF: 0.00559

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

Dec 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.0
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs200930725; hg19: chrX-152018780;