X-152846394-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015922.3(NSDHL):c.70A>G(p.Lys24Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K24R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.506

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116732925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.70A>G	p.Lys24Glu	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.70A>G	p.Lys24Glu	missense_variant	3/9
NSDHL	XM_017029564.2	c.118A>G	p.Lys40Glu	missense_variant	2/8
NSDHL	XM_011531178.3	c.70A>G	p.Lys24Glu	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.70A>G	p.Lys24Glu	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.70A>G	p.Lys24Glu	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1	c.70A>G	p.Lys24Glu	missense_variant	3/8	3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 02, 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1479062). This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 24 of the NSDHL protein (p.Lys24Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	3.4
Dann	Benign	0.93
DEOGEN2	Benign	0.27	T;T;T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.32	T;.;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.024	D;D;D
Sift4G	Benign	0.071	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.16
MutPred		0.32		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		0.67
MPC		0.30
ClinPred		0.091	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-152014938;