X-152846349-A-G

Position:

chrX-152846349-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015922.3(NSDHL):c.25A>G(p.Met9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,209,045 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,594 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0044 ( 1 hom., 181 hem., cov: 24)

Exomes 𝑓: 0.0038 ( 16 hom. 1413 hem. )

Consequence

NSDHL
NM_015922.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.31

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0054329038).

BP6

Variant X-152846349-A-G is Benign according to our data. Variant chrX-152846349-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-152846349-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00442 (498/112640) while in subpopulation NFE AF= 0.00578 (308/53324). AF 95% confidence interval is 0.00525. There are 1 homozygotes in gnomad4. There are 181 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 181 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	2/8	ENST00000370274.8	NP_057006.1	Q15738A0A384NPZ7
NSDHL	NM_001129765.2 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	3/9		NP_001123237.1	Q15738A0A384NPZ7
NSDHL	XM_017029564.2 linkuse as main transcript	c.73A>G	p.Met25Val	missense_variant	2/8		XP_016885053.1
NSDHL	XM_011531178.3 linkuse as main transcript	c.25A>G	p.Met9Val	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.25A>G	p.Met9Val	missense_variant	2/8	1	NM_015922.3	ENSP00000359297.3	Q15738
NSDHL	ENST00000440023.5 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	3/9	5		ENSP00000391854.1	Q15738
NSDHL	ENST00000432467.1 linkuse as main transcript	c.25A>G	p.Met9Val	missense_variant	3/8	3		ENSP00000396266.1	C9JDR0

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

499

AN:

112588

Hom.:

Cov.:

AF XY:

0.00521

AC XY:

181

AN XY:

34752

show subpopulations

Gnomad AFR

AF:

0.000291

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00271

Gnomad ASJ

AF:

0.0102

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.00578

Gnomad OTH

AF:

0.00723

GnomAD3 exomes

AF:

0.00523

AC:

960

AN:

183455

Hom.:

AF XY:

0.00515

AC XY:

350

AN XY:

67901

show subpopulations

Gnomad AFR exome

AF:

0.000304

Gnomad AMR exome

AF:

0.00135

Gnomad ASJ exome

AF:

0.00962

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0222

Gnomad NFE exome

AF:

0.00573

Gnomad OTH exome

AF:

0.00508

GnomAD4 exome

AF:

0.00376

AC:

4124

AN:

1096405

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

1413

AN XY:

361811

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0218

Gnomad4 NFE exome

AF:

0.00335

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.00442

AC:

498

AN:

112640

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

181

AN XY:

34814

show subpopulations

Gnomad4 AFR

AF:

0.000290

Gnomad4 AMR

AF:

0.00271

Gnomad4 ASJ

AF:

0.0102

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.00578

Gnomad4 OTH

AF:

0.00714

Alfa

AF:

0.00513

Hom.:

210

Bravo

AF:

0.00288

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00450

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00505

AC:

ExAC

AF:

0.00502

AC:

609

EpiCase

AF:

0.00414

EpiControl

AF:

0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.0040

DANN

Benign

0.34

DEOGEN2

Benign

0.26

T;T;T

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.33

T;.;T

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.39

N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.65

T;T;T

Sift4G

Benign

0.25

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.15

MVP

0.57

MPC

0.22

ClinPred

0.0024

GERP RS

-6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.30

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