X-152846342-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015922.3(NSDHL):c.18C>G(p.Ser6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,398 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. 14/19 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. S6C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000017 (0 hom. 3 hem.)
  • Failed GnomAD Quality Control
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.633

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025075287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.18C>G	p.Ser6Arg	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.18C>G	p.Ser6Arg	missense_variant	3/9
NSDHL	XM_017029564.2	c.66C>G	p.Ser22Arg	missense_variant	2/8
NSDHL	XM_011531178.3	c.18C>G	p.Ser6Arg	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.18C>G	p.Ser6Arg	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.18C>G	p.Ser6Arg	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1	c.18C>G	p.Ser6Arg	missense_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112398 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34566

Gnomad AFR AF: 0.0000324

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000174 AC: 19 AN: 1093803 Hom.: 0 Cov.: 29 AF XY: 0.00000834 AC XY: 3 AN XY: 359651

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: 0.000199

Gnomad4 NFE exome AF: 0.0000119

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112398 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34566

Gnomad4 AFR AF: 0.0000324

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: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ExAC AF: 0.000700 AC: 85

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

Jun 08, 2022

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 6 of the NSDHL protein (p.Ser6Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NSDHL-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; 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. 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	0.15
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.34
Dann	Benign	0.81
DEOGEN2	Benign	0.26	T;T;T
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.55	T;.;T
MetaRNN	Benign	0.025	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
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		0.58
MPC		0.24
ClinPred		0.0078	T
GERP RS		-4.7
Varity_R		0.11
gMVP		0.38

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

Other links and lift over

dbSNP: rs782233195; hg19: chrX-152014886;