rs782181497

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The ENST00000370274.8(NSDHL):c.904T>C(p.Tyr302His) variant causes a missense change. The variant allele was found at a frequency of 0.00000826 in 1,210,534 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y302C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000082 ( 0 hom. 1 hem. )

Consequence

NSDHL
ENST00000370274.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.54

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.40502447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NSDHL	NM_015922.3 linkuse as main transcript	c.904T>C	p.Tyr302His	missense_variant	8/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2 linkuse as main transcript	c.904T>C	p.Tyr302His	missense_variant	9/9		NP_001123237.1
NSDHL	XM_017029564.2 linkuse as main transcript	c.952T>C	p.Tyr318His	missense_variant	8/8		XP_016885053.1
NSDHL	XM_011531178.3 linkuse as main transcript	c.904T>C	p.Tyr302His	missense_variant	10/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8 linkuse as main transcript	c.904T>C	p.Tyr302His	missense_variant	8/8	1	NM_015922.3	ENSP00000359297	P1
NSDHL	ENST00000440023.5 linkuse as main transcript	c.904T>C	p.Tyr302His	missense_variant	9/9	5		ENSP00000391854	P1

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112503

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34639

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183391

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67833

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000524

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000820

AC:

AN:

1098031

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

363385

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000284

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.00000713

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112503

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34639

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.00

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:

0.00000378

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2016

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 436070). This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. This variant is present in population databases (rs782181497, gnomAD 0.006%), including at least one homozygous and/or hemizygous individual. This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 302 of the NSDHL protein (p.Tyr302His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;.

M_CAP

Benign

0.066

MetaRNN

Benign

0.41

T;T

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.2

M;M

MutationTaster

Benign

0.95

D;D

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.47

Sift

Benign

0.53

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.99

D;D

Vest4

0.26

MutPred

0.52

Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);

MVP

0.86

MPC

0.28

ClinPred

0.47

GERP RS

4.1

Varity_R

0.20

gMVP

0.90

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