rs137853862

Variant names:

• chrX-152858872-G-A
• rs137853862
• NM_015922.3:c.370G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015922.3(NSDHL):​c.370G>A​(p.Gly124Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.48
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• CK syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994

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.370G>A	p.Gly124Ser	missense	Exon 4 of 8	NP_057006.1	A0A384NPZ7
	NSDHL	NM_001129765.2		c.370G>A	p.Gly124Ser	missense	Exon 5 of 9	NP_001123237.1	Q15738
	NSDHL	NM_001441099.1		c.370G>A	p.Gly124Ser	missense	Exon 6 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.370G>A	p.Gly124Ser	missense	Exon 4 of 8	ENSP00000359297.3	Q15738
	NSDHL	ENST00000915682.1		c.406G>A	p.Gly136Ser	missense	Exon 5 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.370G>A	p.Gly124Ser	missense	Exon 5 of 9	ENSP00000391854.1	Q15738

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.5
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.99		Gain of helix (P = 0.2059)
MVP		1.0
MPC		0.81
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853862; hg19: chrX-152027416;