X-152865903-C-T

Variant names:

• chrX-152865903-C-T
• rs104894902
• NM_015922.3:c.628C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015922.3(NSDHL):​c.628C>T​(p.Gln210*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q210Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.00
• 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P
• CK syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-152865903-C-T is Pathogenic according to our data. Variant chrX-152865903-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 11428.Status of the report is no_assertion_criteria_provided, 0 stars.

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.628C>T	p.Gln210*	stop_gained	Exon 6 of 8	NP_057006.1
	NSDHL	NM_001129765.2		c.628C>T	p.Gln210*	stop_gained	Exon 7 of 9	NP_001123237.1
	NSDHL	NM_001441099.1		c.628C>T	p.Gln210*	stop_gained	Exon 8 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.628C>T	p.Gln210*	stop_gained	Exon 6 of 8	ENSP00000359297.3
	NSDHL	ENST00000915682.1		c.664C>T	p.Gln222*	stop_gained	Exon 7 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.628C>T	p.Gln210*	stop_gained	Exon 7 of 9	ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Child syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		5.0
Vest4		0.95
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs104894902; hg19: chrX-152034447;