rs144110486

Variant names:

• chrX-152868895-T-A
• rs144110486
• NM_015922.3:c.901T>A

Your query was ambiguous. Multiple possible variants found:

• chrX-152868895-T-A
• chrX-152868895-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015922.3(NSDHL):​c.901T>A​(p.Tyr301Asn) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y301H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89
• Publications: 1 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.907

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.901T>A	p.Tyr301Asn	missense_variant	Exon 8 of 8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.901T>A	p.Tyr301Asn	missense_variant	Exon 9 of 9		NP_001123237.1
NSDHL	NM_001441099.1	c.901T>A	p.Tyr301Asn	missense_variant	Exon 10 of 10		NP_001428028.1
NSDHL	XM_017029564.2	c.949T>A	p.Tyr317Asn	missense_variant	Exon 8 of 8		XP_016885053.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NSDHL	ENST00000370274.8	c.901T>A	p.Tyr301Asn	missense_variant	Exon 8 of 8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.901T>A	p.Tyr301Asn	missense_variant	Exon 9 of 9	5		ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NSDHL c.901T>A (p.Tyr301Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183382 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.901T>A in individuals affected with NSDHL-Related Disorder and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;.
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.078	T;T
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.56		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);
MVP		0.92
MPC		1.0
ClinPred		0.99	D
GERP RS		4.1
Varity_R		0.77
gMVP		0.92
Mutation Taster		=48/52	disease causing

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: rs144110486; hg19: chrX-152037439;