X-152865819-G-C

Variant names:

• chrX-152865819-G-C
• rs104894904
• NM_015922.3:c.544G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• 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: 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: Likely_pathogenic. The variant received 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 VariationId is 11430.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	NM_015922.3	MANE Select	c.544G>C	p.Ala182Pro	missense splice_region	Exon 6 of 8	NP_057006.1
	NSDHL	NM_001129765.2		c.544G>C	p.Ala182Pro	missense splice_region	Exon 7 of 9	NP_001123237.1
	NSDHL	NM_001441099.1		c.544G>C	p.Ala182Pro	missense splice_region	Exon 8 of 10	NP_001428028.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NSDHL	ENST00000370274.8	TSL:1 MANE Select	c.544G>C	p.Ala182Pro	missense splice_region	Exon 6 of 8	ENSP00000359297.3
	NSDHL	ENST00000915682.1		c.580G>C	p.Ala194Pro	missense splice_region	Exon 7 of 9	ENSP00000585741.1
	NSDHL	ENST00000440023.5	TSL:5	c.544G>C	p.Ala182Pro	missense splice_region	Exon 7 of 9	ENSP00000391854.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Child syndrome (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.63
Sift	Benign	0.080	T
Sift4G	Benign	0.11	T
Polyphen		0.40	B
Vest4		0.56
MutPred		0.90		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
Mutation Taster		=36/64	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104894904; hg19: chrX-152034363;