X-152865819-G-C

Position:

• chrX-152865819-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_015922.3(NSDHL):​c.544G>C​(p.Ala182Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 missense, splice_region
• Scores: Splicing: ADA: 0.01452
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.54

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant X-152865819-G-C is Pathogenic according to our data. Variant chrX-152865819-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 11430.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	6/8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	7/9		NP_001123237.1
NSDHL	XM_017029564.2	c.592G>C	p.Ala198Pro	missense_variant, splice_region_variant	6/8		XP_016885053.1
NSDHL	XM_011531178.3	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	8/10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	6/8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	7/9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.544G>C	p.Ala182Pro	missense_variant, splice_region_variant	7/8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Child syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;D;D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;.;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.5	M;M;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.080	T;T;T
Sift4G	Benign	0.11	T;T;T
Polyphen		0.40	B;B;.
Vest4		0.56
MutPred		0.90		Loss of stability (P = 0.0529);Loss of stability (P = 0.0529);Loss of stability (P = 0.0529);
MVP		1.0
MPC		0.59
ClinPred		0.47	T
GERP RS		3.0
Varity_R		0.92
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.015
dbscSNV1_RF	Benign	0.30
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: -41

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894904; hg19: chrX-152034363;