Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015922.3(NSDHL):c.727G>A(p.Val243Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

NSDHL
NM_015922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.71

Publications

1 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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.898

PP5

Variant X-152867611-G-A is Pathogenic according to our data. Variant chrX-152867611-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 159453.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015922.3. 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.727G>A	p.Val243Met	missense	Exon 7 of 8	NP_057006.1
NSDHL	NM_001129765.2		c.727G>A	p.Val243Met	missense	Exon 8 of 9	NP_001123237.1
NSDHL	NM_001441099.1		c.727G>A	p.Val243Met	missense	Exon 9 of 10	NP_001428028.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.727G>A	p.Val243Met	missense	Exon 7 of 8	ENSP00000359297.3
NSDHL	ENST00000440023.5	TSL:5	c.727G>A	p.Val243Met	missense	Exon 8 of 9	ENSP00000391854.1
NSDHL	ENST00000432467.1	TSL:3	c.727G>A	p.Val243Met	missense	Exon 8 of 8	ENSP00000396266.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Child syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

PhyloP100

9.7

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.90

MutPred

0.69

Loss of catalytic residue at V243 (P = 0.0053)

MVP

0.98

MPC

0.81

ClinPred

1.0

GERP RS

5.3

Varity_R

0.96

gMVP

0.92

Mutation Taster

=47/53

disease causing (ClinVar)

(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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rs587784224

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over