X-152869048-C-T

Position:

• chrX-152869048-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_015922.3(NSDHL):​c.1054C>T​(p.Leu352Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,210,785 control chromosomes in the GnomAD database, including 23 homozygotes. There are 2,137 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 0.0045 (1 hom., 153 hem., cov: 23)
  • Exomes 𝑓: 0.0059 (22 hom. 1984 hem.)
• Consequence: NSDHL NM_015922.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.34

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-152869048-C-T is Benign according to our data. Variant chrX-152869048-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-152869048-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00454 (512/112688) while in subpopulation NFE AF= 0.0071 (378/53264). AF 95% confidence interval is 0.00651. There are 1 homozygotes in gnomad4. There are 153 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 153 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.1054C>T	p.Leu352Leu	synonymous_variant	8/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.1054C>T	p.Leu352Leu	synonymous_variant	9/9		NP_001123237.1
NSDHL	XM_017029564.2	c.1102C>T	p.Leu368Leu	synonymous_variant	8/8		XP_016885053.1
NSDHL	XM_011531178.3	c.1054C>T	p.Leu352Leu	synonymous_variant	10/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.1054C>T	p.Leu352Leu	synonymous_variant	8/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.1054C>T	p.Leu352Leu	synonymous_variant	9/9	5		ENSP00000391854.1

Frequencies

GnomAD3 genomes AF: 0.00456 AC: 514 AN: 112637 Hom.: 1 Cov.: 23 AF XY: 0.00440 AC XY: 153 AN XY: 34787

Gnomad AFR AF: 0.000903

Gnomad AMI AF: 0.00873

Gnomad AMR AF: 0.00476

Gnomad ASJ AF: 0.00982

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00183

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.00710

Gnomad OTH AF: 0.00462

GnomAD3 exomes AF: 0.00477 AC: 874 AN: 183245 Hom.: 3 AF XY: 0.00447 AC XY: 303 AN XY: 67725

Gnomad AFR exome AF: 0.000684

Gnomad AMR exome AF: 0.00511

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00131

Gnomad FIN exome AF: 0.00156

Gnomad NFE exome AF: 0.00700

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00589 AC: 6468 AN: 1098097 Hom.: 22 Cov.: 31 AF XY: 0.00546 AC XY: 1984 AN XY: 363453

Gnomad4 AFR exome AF: 0.000720

Gnomad4 AMR exome AF: 0.00491

Gnomad4 ASJ exome AF: 0.00820

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00129

Gnomad4 FIN exome AF: 0.00220

Gnomad4 NFE exome AF: 0.00667

Gnomad4 OTH exome AF: 0.00631

GnomAD4 genome AF: 0.00454 AC: 512 AN: 112688 Hom.: 1 Cov.: 23 AF XY: 0.00439 AC XY: 153 AN XY: 34848

Gnomad4 AFR AF: 0.000901

Gnomad4 AMR AF: 0.00476

Gnomad4 ASJ AF: 0.00982

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00183

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00710

Gnomad4 OTH AF: 0.00457

Alfa AF: 0.00544 Hom.: 46

Bravo AF: 0.00463

EpiCase AF: 0.00834

EpiControl AF: 0.00818

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 11, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -

Child syndrome;C3151781:CK syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 19, 2021

- -

Connective tissue disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2019

- -

CK syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.9
DANN	Benign	0.57

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: rs142351862; hg19: chrX-152037592;