X-152846368-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_015922.3(NSDHL):c.44G>A(p.Arg15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,209,505 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 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. R15W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000066 (0 hom. 26 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.856

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10371074).
• BP6: Variant X-152846368-G-A is Benign according to our data. Variant chrX-152846368-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1341846.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000267 (3/112402) while in subpopulation NFE AF= 0.0000563 (3/53308). 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.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.44G>A	p.Arg15Gln	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.44G>A	p.Arg15Gln	missense_variant	3/9
NSDHL	XM_017029564.2	c.92G>A	p.Arg31Gln	missense_variant	2/8
NSDHL	XM_011531178.3	c.44G>A	p.Arg15Gln	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.44G>A	p.Arg15Gln	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.44G>A	p.Arg15Gln	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1	c.44G>A	p.Arg15Gln	missense_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112402 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34576

Gnomad AFR AF: 0.00

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: 0.0000563

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000382 AC: 7 AN: 183452 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000656 AC: 72 AN: 1097103 Hom.: 0 Cov.: 29 AF XY: 0.0000717 AC XY: 26 AN XY: 362473

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000785

Gnomad4 OTH exome AF: 0.0000651

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112402 Hom.: 0 Cov.: 24 AF XY: 0.0000289 AC XY: 1 AN XY: 34576

Gnomad4 AFR AF: 0.00

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: 0.0000563

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000533 Hom.: 3

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CK syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 29, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	0.034
Dann	Benign	0.90
DEOGEN2	Benign	0.26	T;T;T
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.47	T;.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.26	N;N;N
REVEL	Benign	0.21
Sift	Benign	0.38	T;T;T
Sift4G	Benign	0.74	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.092
MVP		0.62
MPC		0.25
ClinPred		0.021	T
GERP RS		-4.8
Varity_R		0.027
gMVP		0.35

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: rs200748828; hg19: chrX-152014912; COSMIC: COSV64745148;