X-152846349-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.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. 13/19 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:4
• Conservation: PhyloP100: -1.31

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=0.0054329038).
• BP6: Variant X-152846349-A-G is Benign according to our data. Variant chrX-152846349-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 159451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-152846349-A-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 181 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NSDHL	NM_015922.3	c.25A>G	p.Met9Val	missense_variant	2/8	ENST00000370274.8
NSDHL	NM_001129765.2	c.25A>G	p.Met9Val	missense_variant	3/9
NSDHL	XM_017029564.2	c.73A>G	p.Met25Val	missense_variant	2/8
NSDHL	XM_011531178.3	c.25A>G	p.Met9Val	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NSDHL	ENST00000370274.8	c.25A>G	p.Met9Val	missense_variant	2/8	1	NM_015922.3	P1
NSDHL	ENST00000440023.5	c.25A>G	p.Met9Val	missense_variant	3/9	5		P1
NSDHL	ENST00000432467.1	c.25A>G	p.Met9Val	missense_variant	3/8	3

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 499 AN: 112588 Hom.: 1 Cov.: 24 AF XY: 0.00521 AC XY: 181 AN XY: 34752

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

GnomAD3 exomes AF: 0.00523 AC: 960 AN: 183455 Hom.: 7 AF XY: 0.00515 AC XY: 350 AN XY: 67901

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 SAS 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

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.00139

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.0218

Gnomad4 NFE exome AF: 0.00335

Gnomad4 OTH exome AF: 0.00356

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

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00271

Gnomad4 ASJ AF: 0.0102

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0183

Gnomad4 NFE AF: 0.00578

Gnomad4 OTH AF: 0.00714

Alfa AF: 0.00513 Hom.: 210

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 17, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 12, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

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;T;T
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T;.;T
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.39	N;N;N
REVEL	Uncertain	0.29
Sift	Benign	0.65	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0	B;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

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: rs35529894; hg19: chrX-152014893;