X-152846343-G-A

Position:

chrX-152846343-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6_ModerateBS1BS2

The NM_015922.3(NSDHL):c.19G>A(p.Glu7Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,207,478 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000034 ( 0 hom. 13 hem. )

Consequence

NSDHL
NM_015922.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.84

Variant links:

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]

NSDHL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13119668).

BP6

Variant X-152846343-G-A is Benign according to our data. Variant chrX-152846343-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3301142.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-152846343-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000338 (37/1095047) while in subpopulation EAS AF= 0.0000662 (2/30191). AF 95% confidence interval is 0.0000292. There are 0 homozygotes in gnomad4_exome. There are 13 alleles in male gnomad4_exome subpopulation. Median coverage is 29. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	2/8	ENST00000370274.8	NP_057006.1	Q15738A0A384NPZ7
NSDHL	NM_001129765.2 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	3/9		NP_001123237.1	Q15738A0A384NPZ7
NSDHL	XM_017029564.2 linkuse as main transcript	c.67G>A	p.Glu23Lys	missense_variant	2/8		XP_016885053.1
NSDHL	XM_011531178.3 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	4/10		XP_011529480.1	Q15738A0A384NPZ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NSDHL	ENST00000370274.8 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	2/8	1	NM_015922.3	ENSP00000359297.3	Q15738
NSDHL	ENST00000440023.5 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	3/9	5		ENSP00000391854.1	Q15738
NSDHL	ENST00000432467.1 linkuse as main transcript	c.19G>A	p.Glu7Lys	missense_variant	3/8	3		ENSP00000396266.1	C9JDR0

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112431

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

34595

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000939

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000279

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000382

AC:

AN:

183449

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

67891

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000488

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000338

AC:

AN:

1095047

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

360491

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000405

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112431

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

34595

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.0000939

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000279

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.37

CADD

Benign

6.0

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;T;T

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.52

T;.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.53

N;N;N

REVEL

Benign

0.24

Sift

Benign

0.074

T;T;T

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

0.0040

B;B;.

Vest4

0.35

MutPred

0.30

Gain of ubiquitination at E7 (P = 0.0018);Gain of ubiquitination at E7 (P = 0.0018);Gain of ubiquitination at E7 (P = 0.0018);

MVP

0.74

MPC

0.24

ClinPred

0.043

GERP RS

3.3

Varity_R

0.058

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over