rs121909833

Variant names:

• chrX-152867576-GGAA-G
• rs121909833
• NM_015922.3:c.696_698delGAA

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_015922.3(NSDHL):​c.696_698delGAA​(p.Lys232del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: NSDHL NM_015922.3 disruptive_inframe_deletion
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 4.98
• Publications: 4 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_015922.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-152867576-GGAA-G is Pathogenic according to our data. Variant chrX-152867576-GGAA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 21268.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 7 of 8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 8 of 9		NP_001123237.1
NSDHL	NM_001441099.1	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 9 of 10		NP_001428028.1
NSDHL	XM_017029564.2	c.744_746delGAA	p.Lys248del	disruptive_inframe_deletion	Exon 7 of 8		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 7 of 8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 8 of 9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.696_698delGAA	p.Lys232del	disruptive_inframe_deletion	Exon 8 of 8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

CK syndrome Pathogenic:1 Other:1

Dec 10, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.0
Mutation Taster		=71/29	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: rs121909833; hg19: chrX-152036120;