X-152850288-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_015922.3(NSDHL):c.132T>G(p.Gly44=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (27281 hom., 27862 hem., cov: 23)
  • Exomes 𝑓: 0.87 (279620 hom. 318527 hem.)
  • Failed GnomAD Quality Control
• Consequence: NSDHL NM_015922.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.673

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-152850288-T-G is Benign according to our data. Variant chrX-152850288-T-G is described in ClinVar as [Benign]. Clinvar id is 159450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-152850288-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.673 with no splicing effect.
• BS2: High Homozygotes in GnomAd at 27288 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.132T>G	p.Gly44=	synonymous_variant	3/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.132T>G	p.Gly44=	synonymous_variant	4/9
NSDHL	XM_017029564.2	c.180T>G	p.Gly60=	synonymous_variant	3/8
NSDHL	XM_011531178.3	c.132T>G	p.Gly44=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.132T>G	p.Gly44=	synonymous_variant	3/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.132T>G	p.Gly44=	synonymous_variant	4/9	5		P1
NSDHL	ENST00000432467.1	c.132T>G	p.Gly44=	synonymous_variant	4/8	3

Frequencies

GnomAD3 genomes AF: 0.838 AC: 92769 AN: 110674 Hom.: 27288 Cov.: 23 AF XY: 0.845 AC XY: 27795 AN XY: 32886

Gnomad AFR AF: 0.740

Gnomad AMI AF: 0.960

Gnomad AMR AF: 0.909

Gnomad ASJ AF: 0.920

Gnomad EAS AF: 0.915

Gnomad SAS AF: 0.930

Gnomad FIN AF: 0.841

Gnomad MID AF: 0.870

Gnomad NFE AF: 0.865

Gnomad OTH AF: 0.856

GnomAD3 exomes AF: 0.882 AC: 161742 AN: 183420 Hom.: 44885 AF XY: 0.886 AC XY: 60110 AN XY: 67866

Gnomad AFR exome AF: 0.746

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.918

Gnomad EAS exome AF: 0.916

Gnomad SAS exome AF: 0.941

Gnomad FIN exome AF: 0.852

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.880

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.874 AC: 959053 AN: 1097942 Hom.: 279620 Cov.: 48 AF XY: 0.877 AC XY: 318527 AN XY: 363394

Gnomad4 AFR exome AF: 0.744

Gnomad4 AMR exome AF: 0.937

Gnomad4 ASJ exome AF: 0.915

Gnomad4 EAS exome AF: 0.945

Gnomad4 SAS exome AF: 0.939

Gnomad4 FIN exome AF: 0.847

Gnomad4 NFE exome AF: 0.868

Gnomad4 OTH exome AF: 0.872

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.838 AC: 92823 AN: 110730 Hom.: 27281 Cov.: 23 AF XY: 0.846 AC XY: 27862 AN XY: 32952

Gnomad4 AFR AF: 0.740

Gnomad4 AMR AF: 0.909

Gnomad4 ASJ AF: 0.920

Gnomad4 EAS AF: 0.915

Gnomad4 SAS AF: 0.929

Gnomad4 FIN AF: 0.841

Gnomad4 NFE AF: 0.865

Gnomad4 OTH AF: 0.857

Alfa AF: 0.871 Hom.: 15588

Bravo AF: 0.841

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 02, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Child syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

CK syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	4.9
Dann	Benign	0.54

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: rs5969919; hg19: chrX-152018832; COSMIC: COSV64743481;