X-152846395-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1

The NM_015922.3(NSDHL):c.71A>G(p.Lys24Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000563 in 1,206,950 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 18 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K24E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000058 ( 0 hom. 17 hem. )

Consequence

NSDHL
NM_015922.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.541

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 Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09302643).

BP6

Variant X-152846395-A-G is Benign according to our data. Variant chrX-152846395-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1933287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000355 (4/112712) while in subpopulation EAS AF= 0.000277 (1/3611). AF 95% confidence interval is 0.0000149. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NSDHL	NM_015922.3 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	3/9
NSDHL	XM_017029564.2 linkuse as main transcript	c.119A>G	p.Lys40Arg	missense_variant	2/8
NSDHL	XM_011531178.3 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
NSDHL	ENST00000370274.8 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1 linkuse as main transcript	c.71A>G	p.Lys24Arg	missense_variant	3/8	3

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112712

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34850

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:

0.000277

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000562

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183429

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67873

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000585

AC:

AN:

1094238

Hom.:

Cov.:

AF XY:

0.0000473

AC XY:

AN XY:

359666

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

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:

0.0000692

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000355

AC:

AN:

112712

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34850

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000277

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000562

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 28, 2022	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 24 of the NSDHL protein (p.Lys24Arg). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. This variant is present in population databases (rs201339444, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	NSDHL: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.57

Cadd

Benign

1.2

Dann

Benign

0.54

DEOGEN2

Benign

0.26

T;T;T

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.33

T;.;T

M_CAP

Benign

0.020

MetaRNN

Benign

0.093

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.19

N;N;N

REVEL

Benign

0.22

Sift

Benign

0.16

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.13

MutPred

0.29

Loss of ubiquitination at K24 (P = 0.0039);Loss of ubiquitination at K24 (P = 0.0039);Loss of ubiquitination at K24 (P = 0.0039);

MVP

0.57

MPC

0.17

ClinPred

0.016

GERP RS

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.042

gMVP

0.19

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