X-152865819-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The ENST00000370274.8(NSDHL):c.544G>A(p.Ala182Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000883 in 113,227 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A182P) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 24)

Consequence

NSDHL
ENST00000370274.8 missense, splice_region

Scores

Splicing: ADA: 0.0008968

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.54

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-152865819-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11430.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.38112855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000370274.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSDHL	NM_015922.3	MANE Select	c.544G>A	p.Ala182Thr	missense splice_region	Exon 6 of 8	NP_057006.1
NSDHL	NM_001129765.2		c.544G>A	p.Ala182Thr	missense splice_region	Exon 7 of 9	NP_001123237.1
NSDHL	NM_001441099.1		c.544G>A	p.Ala182Thr	missense splice_region	Exon 8 of 10	NP_001428028.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.544G>A	p.Ala182Thr	missense splice_region	Exon 6 of 8	ENSP00000359297.3
NSDHL	ENST00000440023.5	TSL:5	c.544G>A	p.Ala182Thr	missense splice_region	Exon 7 of 9	ENSP00000391854.1
NSDHL	ENST00000432467.1	TSL:3	c.544G>A	p.Ala182Thr	missense splice_region	Exon 7 of 8	ENSP00000396266.1

Frequencies

GnomAD3 genomes

AF:

0.00000883

AC:

AN:

113227

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000357

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000883

AC:

AN:

113227

Hom.:

Cov.:

AF XY:

0.0000283

AC XY:

AN XY:

35365

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31206

American (AMR)

AF:

0.00

AC:

AN:

10808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3582

South Asian (SAS)

AF:

0.000357

AC:

AN:

2799

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53390

Other (OTH)

AF:

0.00

AC:

AN:

1533

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0073

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Uncertain

0.64

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.82

M_CAP

Benign

0.045

MetaRNN

Benign

0.38

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.73

PhyloP100

1.5

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.65

REVEL

Uncertain

0.31

Sift

Benign

0.30

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.10

MutPred

0.63

Loss of stability (P = 0.0885)

MVP

0.94

MPC

0.21

ClinPred

0.067

GERP RS

3.0

Varity_R

0.14

gMVP

0.77

Mutation Taster

=61/39

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00090

dbscSNV1_RF

Benign

0.13

SpliceAI score (max)

0.090

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over