X-7257478-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001320752.2(STS):c.272G>A(p.Trp91Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: STS NM_001320752.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.0670

Genes affected

STS (HGNC:11425): (steroid sulfatase) This gene encodes a multi-pass membrane protein that is localized to the endoplasmic reticulum. It belongs to the sulfatase family and hydrolyzes several 3-beta-hydroxysteroid sulfates, which serve as metabolic precursors for estrogens, androgens, and cholesterol. Mutations in this gene are associated with X-linked ichthyosis (XLI). Alternatively spliced transcript variants resulting from the use of different promoters have been described for this gene (PMID:17601726). [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-7257478-G-A is Pathogenic according to our data. Variant chrX-7257478-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 625856.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STS	NM_001320752.2	c.272G>A	p.Trp91Ter	stop_gained	5/11	ENST00000674429.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STS	ENST00000674429.1	c.272G>A	p.Trp91Ter	stop_gained	5/11		NM_001320752.2	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked ichthyosis with steryl-sulfatase deficiency Pathogenic:2

Pathogenic, no assertion criteria provided	research	FAHD UNIT, Department of Genetics, King Faisal Specialist Hospital and Research Centre	Jan 31, 2019	- -
Pathogenic, criteria provided, single submitter	research	Faculty of Allied and Health Sciences, Imperial College of Business Studies	Apr 30, 2019	Sanger sequencing identified a novel hemizygous nonsense mutation, chromosome X:7,175,519 (c.287G>A; p.W96*), in exon 4 of STS gene in the proband and all other affected male individuals, while this deleterious mutation was not detected in the normal controls. We report genetic findings of a large Pakistani family with XLI using direct DNA sequencing of the entire coding region of STS. The clinical manifestations occurred early in life and involved generalized dryness and scaling of the skin with polygonal, regular dark scales of the skin on scalp, posterior ear, neck, trunk and limbs, palms and soles were spared. There were no associated extra-cutaneous features such as shortness, hyposmia, cryptorchidism, photophobia, corneal opacities, autism, intellectual disability or attention deficit hyperactivity disorder. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	23
Dann	Benign	0.92
FATHMM_MKL	Benign	0.014	N
MutationTaster	Benign	1.0	A
Vest4		0.88
GERP RS		-3.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1463414987; hg19: chrX-7175519;