X-152869031-C-CCATG

Position:

• chrX-152869031-C-CCATG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_015922.3(NSDHL):​c.1038_1041dupCATG​(p.Gly348fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.265

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0713 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-152869031-C-CCATG is Pathogenic according to our data. Variant chrX-152869031-C-CCATG is described in ClinVar as [Pathogenic]. Clinvar id is 211748.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.1038_1041dupCATG	p.Gly348fs	frameshift_variant	8/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.1038_1041dupCATG	p.Gly348fs	frameshift_variant	9/9		NP_001123237.1
NSDHL	XM_017029564.2	c.1086_1089dupCATG	p.Gly364fs	frameshift_variant	8/8		XP_016885053.1
NSDHL	XM_011531178.3	c.1038_1041dupCATG	p.Gly348fs	frameshift_variant	10/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.1038_1041dupCATG	p.Gly348fs	frameshift_variant	8/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.1038_1041dupCATG	p.Gly348fs	frameshift_variant	9/9	5		ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Child syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797045835; hg19: chrX-152037575;