X-152846407-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.83A>G(p.Asp28Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000183 in 1,203,627 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 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 0.00013 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 4 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.377

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=0.010177553).
• BP6: Variant X-152846407-A-G is Benign according to our data. Variant chrX-152846407-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 2075424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000133 (15/112851) while in subpopulation AFR AF= 0.000483 (15/31080). AF 95% confidence interval is 0.000297. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.83A>G	p.Asp28Gly	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.83A>G	p.Asp28Gly	missense_variant	3/9
NSDHL	XM_017029564.2	c.131A>G	p.Asp44Gly	missense_variant	2/8
NSDHL	XM_011531178.3	c.83A>G	p.Asp28Gly	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.83A>G	p.Asp28Gly	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.83A>G	p.Asp28Gly	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1	c.83A>G	p.Asp28Gly	missense_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 15 AN: 112798 Hom.: 0 Cov.: 23 AF XY: 0.000200 AC XY: 7 AN XY: 34930

Gnomad AFR AF: 0.000484

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: 0.0000709 AC: 13 AN: 183386 Hom.: 0 AF XY: 0.000118 AC XY: 8 AN XY: 67828

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000642 AC: 7 AN: 1090776 Hom.: 0 Cov.: 29 AF XY: 0.0000112 AC XY: 4 AN XY: 356358

Gnomad4 AFR exome AF: 0.000228

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: 0.0000247

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.000133 AC: 15 AN: 112851 Hom.: 0 Cov.: 23 AF XY: 0.000200 AC XY: 7 AN XY: 34993

Gnomad4 AFR AF: 0.000483

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

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.0000982

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Benign/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

Feb 28, 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

Benign, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	0.53
Dann	Benign	0.95
DEOGEN2	Benign	0.27	T;T;T
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.42	T;.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.060	N;N;N
REVEL	Benign	0.20
Sift	Benign	0.048	D;D;D
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
MVP		0.53
MPC		0.28
ClinPred		0.013	T
GERP RS		-2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144891548; hg19: chrX-152014951;