rs184536370

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.267+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,208,037 control chromosomes in the GnomAD database, including 3 homozygotes. There are 281 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00084 ( 0 hom., 41 hem., cov: 23)

Exomes 𝑓: 0.00067 ( 3 hom. 240 hem. )

Consequence

NSDHL
NM_015922.3 splice_region, intron

Scores

Splicing: ADA: 0.0001858

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.835

Publications

0 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 (BayesDel_noAF=-0.84).

BP6

Variant X-152850430-G-A is Benign according to our data. Variant chrX-152850430-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211749.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 = 0.000837 (94/112358) while in subpopulation NFE AF = 0.000957 (51/53282). AF 95% confidence interval is 0.000748. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 3 of 7	ENST00000370274.8	NP_057006.1	Q15738A0A384NPZ7
NSDHL	NM_001129765.2 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 4 of 8		NP_001123237.1	Q15738A0A384NPZ7
NSDHL	NM_001441099.1 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 5 of 9		NP_001428028.1
NSDHL	XM_017029564.2 link	c.315+7G>A	splice_region_variant, intron_variant	Intron 3 of 7		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NSDHL	ENST00000370274.8 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 3 of 7	1	NM_015922.3	ENSP00000359297.3	Q15738
NSDHL	ENST00000440023.5 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 4 of 8	5		ENSP00000391854.1	Q15738
NSDHL	ENST00000432467.1 link	c.267+7G>A	splice_region_variant, intron_variant	Intron 4 of 7	3		ENSP00000396266.1	C9JDR0

Frequencies

GnomAD3 genomes

AF:

0.000837

AC:

AN:

112303

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000566

Gnomad ASJ

AF:

0.00188

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00506

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000957

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00140

AC:

257

AN:

183209

AF XY:

0.00118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000766

Gnomad ASJ exome

AF:

0.00241

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00762

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.000669

AC:

733

AN:

1095679

Hom.:

Cov.:

AF XY:

0.000665

AC XY:

240

AN XY:

361075

show subpopulations

African (AFR)

AF:

0.0000759

AC:

AN:

26356

American (AMR)

AF:

0.000625

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00191

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

54066

European-Finnish (FIN)

AF:

0.00666

AC:

270

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4073

European-Non Finnish (NFE)

AF:

0.000438

AC:

368

AN:

839863

Other (OTH)

AF:

0.000739

AC:

AN:

46016

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

104

138

173

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000837

AC:

AN:

112358

Hom.:

Cov.:

AF XY:

0.00119

AC XY:

AN XY:

34516

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30977

American (AMR)

AF:

0.000566

AC:

AN:

10608

Ashkenazi Jewish (ASJ)

AF:

0.00188

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.00

AC:

AN:

2681

European-Finnish (FIN)

AF:

0.00506

AC:

AN:

6124

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000957

AC:

AN:

53282

Other (OTH)

AF:

0.00

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

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:

0.00167

Hom.:

Bravo

AF:

0.000461

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 28, 2015

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability

Benign:1

Nov 13, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

1.3

(source)

DANN

Benign

0.56

PhyloP100

0.83

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00019

dbscSNV1_RF

Benign

0.0

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