X-152850269-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015922.3(NSDHL):c.113A>G(p.Lys38Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,208,409 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00013 (0 hom. 37 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.69

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011539519).
• BP6: Variant X-152850269-A-G is Benign according to our data. Variant chrX-152850269-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2856361.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000891 (10/112225) while in subpopulation EAS AF= 0.00281 (10/3560). AF 95% confidence interval is 0.00152. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.113A>G	p.Lys38Arg	missense_variant	3/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.113A>G	p.Lys38Arg	missense_variant	4/9
NSDHL	XM_017029564.2	c.161A>G	p.Lys54Arg	missense_variant	3/8
NSDHL	XM_011531178.3	c.113A>G	p.Lys38Arg	missense_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.113A>G	p.Lys38Arg	missense_variant	3/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.113A>G	p.Lys38Arg	missense_variant	4/9	5		P1
NSDHL	ENST00000432467.1	c.113A>G	p.Lys38Arg	missense_variant	4/8	3

Frequencies

GnomAD3 genomes AF: 0.0000891 AC: 10 AN: 112171 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34333

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00280

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: 0.000240 AC: 44 AN: 183452 Hom.: 0 AF XY: 0.000147 AC XY: 10 AN XY: 67902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00303

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000129 AC: 141 AN: 1096184 Hom.: 0 Cov.: 29 AF XY: 0.000102 AC XY: 37 AN XY: 361884

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00460

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: 0.0000891 AC: 10 AN: 112225 Hom.: 0 Cov.: 23 AF XY: 0.000145 AC XY: 5 AN XY: 34397

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000982 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NSDHL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	5.7
Dann	Benign	0.76
DEOGEN2	Benign	0.30	T;T;T
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.37	T;.;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.47	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.83	T;T;T
Sift4G	Benign	0.72	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.14
MVP		0.79
MPC		0.18
ClinPred		0.010	T
GERP RS		3.1
Varity_R		0.096
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs192455721; hg19: chrX-152018813;