rs35529894

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 13/20 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

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

CHILD syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
CK syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

NSDHL links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 159451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 181 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3 link	c.25A>G	p.Met9Val	missense_variant	Exon 2 of 8	ENST00000370274.8	NP_057006.1	Q15738A0A384NPZ7
NSDHL	NM_001129765.2 link	c.25A>G	p.Met9Val	missense_variant	Exon 3 of 9		NP_001123237.1	Q15738A0A384NPZ7
NSDHL	NM_001441099.1 link	c.25A>G	p.Met9Val	missense_variant	Exon 4 of 10		NP_001428028.1
NSDHL	XM_017029564.2 link	c.73A>G	p.Met25Val	missense_variant	Exon 2 of 8		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NSDHL	ENST00000370274.8 link	c.25A>G	p.Met9Val	missense_variant	Exon 2 of 8	1	NM_015922.3	ENSP00000359297.3	Q15738
NSDHL	ENST00000440023.5 link	c.25A>G	p.Met9Val	missense_variant	Exon 3 of 9	5		ENSP00000391854.1	Q15738
NSDHL	ENST00000432467.1 link	c.25A>G	p.Met9Val	missense_variant	Exon 3 of 8	3		ENSP00000396266.1	C9JDR0

Frequencies

GnomAD3 genomes

AF:

0.00443

AC:

499

AN:

112588

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00523

AC:

960

AN:

183455

AF XY:

0.00515

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 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

African (AFR)

AF:

0.000190

AC:

AN:

26378

American (AMR)

AF:

0.00139

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

195

AN:

19376

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54127

European-Finnish (FIN)

AF:

0.0218

AC:

885

AN:

40531

Middle Eastern (MID)

AF:

0.00170

AC:

AN:

4128

European-Non Finnish (NFE)

AF:

0.00335

AC:

2818

AN:

840424

Other (OTH)

AF:

0.00356

AC:

164

AN:

46034

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

152

305

457

610

762

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00442

AC:

498

AN:

112640

Hom.:

Cov.:

AF XY:

0.00520

AC XY:

181

AN XY:

34814

show subpopulations

African (AFR)

AF:

0.000290

AC:

AN:

31021

American (AMR)

AF:

0.00271

AC:

AN:

10698

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3572

South Asian (SAS)

AF:

0.00

AC:

AN:

2733

European-Finnish (FIN)

AF:

0.0183

AC:

113

AN:

6191

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00578

AC:

308

AN:

53324

Other (OTH)

AF:

0.00714

AC:

AN:

1541

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00484

Hom.:

211

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

Apr 17, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Nov 29, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.

PhyloP100

-1.3

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over