rs35529894

Variant names:

• chrX-152846349-A-G
• rs35529894
• NM_015922.3:c.25A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015922.3(NSDHL):​c.25A>G​(p.Met9Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,209,045 control chromosomes in the GnomAD database, including 17 homozygotes. There are 1,594 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (1 hom., 181 hem., cov: 24)
  • Exomes 𝑓: 0.0038 (16 hom. 1413 hem.)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.31
• Publications: 3 publications found

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]

NSDHL Gene-Disease associations (from GenCC):

• CHILD syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• CK syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0054329038).
• BP6: Variant X-152846349-A-G is Benign according to our data. Variant chrX-152846349-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 159451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00442 (498/112640) while in subpopulation NFE AF = 0.00578 (308/53324). AF 95% confidence interval is 0.00525. There are 1 homozygotes in GnomAd4. There are 181 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 181 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015922.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	NM_015922.3	MANE Select	c.25A>G	p.Met9Val	missense	Exon 2 of 8	NP_057006.1	A0A384NPZ7
	NSDHL	NM_001129765.2		c.25A>G	p.Met9Val	missense	Exon 3 of 9	NP_001123237.1	Q15738
	NSDHL	NM_001441099.1		c.25A>G	p.Met9Val	missense	Exon 4 of 10	NP_001428028.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.25A>G	p.Met9Val	missense	Exon 2 of 8	ENSP00000359297.3	Q15738
	NSDHL	ENST00000915682.1		c.25A>G	p.Met9Val	missense	Exon 2 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.25A>G	p.Met9Val	missense	Exon 3 of 9	ENSP00000391854.1	Q15738

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 499 AN: 112588 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00271

Gnomad ASJ AF: 0.0102

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00723

GnomAD2 exomes AF: 0.00523 AC: 960 AN: 183455 AF XY: 0.00515

Gnomad AFR exome AF: 0.000304

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00962

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0222

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00508

GnomAD4 exome AF: 0.00376 AC: 4124 AN: 1096405 Hom.: 16 Cov.: 29 AF XY: 0.00391 AC XY: 1413 AN XY: 361811

African (AFR) AF: 0.000190 AC: 5 AN: 26378

American (AMR) AF: 0.00139 AC: 49 AN: 35206

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 195 AN: 19376

East Asian (EAS) AF: 0.00 AC: 0 AN: 30201

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54127

European-Finnish (FIN) AF: 0.0218 AC: 885 AN: 40531

Middle Eastern (MID) AF: 0.00170 AC: 7 AN: 4128

European-Non Finnish (NFE) AF: 0.00335 AC: 2818 AN: 840424

Other (OTH) AF: 0.00356 AC: 164 AN: 46034

GnomAD4 genome AF: 0.00442 AC: 498 AN: 112640 Hom.: 1 Cov.: 24 AF XY: 0.00520 AC XY: 181 AN XY: 34814

African (AFR) AF: 0.000290 AC: 9 AN: 31021

American (AMR) AF: 0.00271 AC: 29 AN: 10698

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 27 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3572

South Asian (SAS) AF: 0.00 AC: 0 AN: 2733

European-Finnish (FIN) AF: 0.0183 AC: 113 AN: 6191

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00578 AC: 308 AN: 53324

Other (OTH) AF: 0.00714 AC: 11 AN: 1541

Alfa AF: 0.00484 Hom.: 211

Bravo AF: 0.00288

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00450 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00505 AC: 34

ExAC AF: 0.00502 AC: 609

EpiCase AF: 0.00414

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.0040
DANN	Benign	0.34
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.3
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.39	N
REVEL	Uncertain	0.29
Sift	Benign	0.65	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.57
MPC		0.22
ClinPred		0.0024	T
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35529894; hg19: chrX-152014893;