rs104894901

Variant names:

• chrX-152865888-G-A
• rs104894901
• NM_015922.3:c.613G>A

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.613G>A​(p.Gly205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 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).

• Frequency: Genomes: not found (cov: 25)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 10.0

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, 0.992
• PP5: Variant X-152865888-G-A is Pathogenic according to our data. Variant chrX-152865888-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11427.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.613G>A	p.Gly205Ser	missense_variant	Exon 6 of 8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.613G>A	p.Gly205Ser	missense_variant	Exon 7 of 9		NP_001123237.1
NSDHL	XM_017029564.2	c.661G>A	p.Gly221Ser	missense_variant	Exon 6 of 8		XP_016885053.1
NSDHL	XM_011531178.3	c.613G>A	p.Gly205Ser	missense_variant	Exon 8 of 10		XP_011529480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.613G>A	p.Gly205Ser	missense_variant	Exon 6 of 8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.613G>A	p.Gly205Ser	missense_variant	Exon 7 of 9	5		ENSP00000391854.1
NSDHL	ENST00000432467.1	c.613G>A	p.Gly205Ser	missense_variant	Exon 7 of 8	3		ENSP00000396266.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Child syndrome Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Feb 14, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.73
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.99		Loss of catalytic residue at G205 (P = 0.0747);Loss of catalytic residue at G205 (P = 0.0747);Loss of catalytic residue at G205 (P = 0.0747);
MVP		0.99
MPC		0.80
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs104894901; hg19: chrX-152034432;