X-152868895-T-C

Variant names:

• chrX-152868895-T-C
• rs144110486
• NM_015922.3:c.901T>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>C​(p.Tyr301His) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y301N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: NSDHL NM_015922.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided 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, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NSDHL	NM_015922.3	c.901T>C	p.Tyr301His	missense_variant	Exon 8 of 8	ENST00000370274.8	NP_057006.1
NSDHL	NM_001129765.2	c.901T>C	p.Tyr301His	missense_variant	Exon 9 of 9		NP_001123237.1
NSDHL	NM_001441099.1	c.901T>C	p.Tyr301His	missense_variant	Exon 10 of 10		NP_001428028.1
NSDHL	XM_017029564.2	c.949T>C	p.Tyr317His	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>C	p.Tyr301His	missense_variant	Exon 8 of 8	1	NM_015922.3	ENSP00000359297.3
NSDHL	ENST00000440023.5	c.901T>C	p.Tyr301His	missense_variant	Exon 9 of 9	5		ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183382 AF XY: 0.00

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:1

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.4	M;M
PhyloP100		7.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Pathogenic	0.81
Sift	Benign	0.040	D;D
Sift4G	Benign	0.14	T;T
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.89
MPC		0.91
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.57
gMVP		0.84
Mutation Taster		=46/54	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;