X-152846340-A-T

Position:

chrX-152846340-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_015922.3(NSDHL):c.16A>T(p.Ser6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,207,713 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

NSDHL
NM_015922.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.169

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10989633).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000177 (2/112776) while in subpopulation AMR AF= 0.000187 (2/10695). AF 95% confidence interval is 0.0000328. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	2/8	ENST00000370274.8	NP_057006.1	Q15738A0A384NPZ7
NSDHL	NM_001129765.2 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	3/9		NP_001123237.1	Q15738A0A384NPZ7
NSDHL	XM_017029564.2 linkuse as main transcript	c.64A>T	p.Ser22Cys	missense_variant	2/8		XP_016885053.1
NSDHL	XM_011531178.3 linkuse as main transcript	c.16A>T	p.Ser6Cys	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.16A>T	p.Ser6Cys	missense_variant	2/8	1	NM_015922.3	ENSP00000359297.3	Q15738
NSDHL	ENST00000440023.5 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	3/9	5		ENSP00000391854.1	Q15738
NSDHL	ENST00000432467.1 linkuse as main transcript	c.16A>T	p.Ser6Cys	missense_variant	3/8	3		ENSP00000396266.1	C9JDR0

Frequencies

GnomAD3 genomes

AF:

0.0000177

AC:

AN:

112776

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34908

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000187

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1094937

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360421

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000177

AC:

AN:

112776

Hom.:

Cov.:

AF XY:

0.0000286

AC XY:

AN XY:

34908

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000187

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2023

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 6 of the NSDHL protein (p.Ser6Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

9.0

DANN

Benign

0.95

DEOGEN2

Benign

0.26

T;T;T

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.61

T;.;T

M_CAP

Benign

0.038

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.55

N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.058

T;T;D

Sift4G

Uncertain

0.058

T;T;T

Polyphen

0.76

P;P;.

Vest4

0.27

MutPred

0.20

Loss of phosphorylation at S6 (P = 0.021);Loss of phosphorylation at S6 (P = 0.021);Loss of phosphorylation at S6 (P = 0.021);

MVP

0.56

MPC

0.34

ClinPred

0.12

GERP RS

-1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.29

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