chrX-7334066-G-A

Variant names:

• chrX-7334066-G-A
• rs137853166
• NM_001320752.2:c.1322G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001320752.2(STS):​c.1322G>A​(p.Cys441Tyr) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: STS NM_001320752.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.03
• Publications: 4 publications found

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]

STS Gene-Disease associations (from GenCC):

• recessive X-linked ichthyosis

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

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, 0.981
• PP5: Variant X-7334066-G-A is Pathogenic according to our data. Variant chrX-7334066-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10553.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320752.2. 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
	STS	NM_001320752.2	MANE Select	c.1322G>A	p.Cys441Tyr	missense	Exon 10 of 11	NP_001307681.2
	STS	NM_001320750.3		c.1358G>A	p.Cys453Tyr	missense	Exon 10 of 11	NP_001307679.1
	STS	NM_001320751.2		c.1358G>A	p.Cys453Tyr	missense	Exon 11 of 12	NP_001307680.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STS	ENST00000674429.1	MANE Select	c.1322G>A	p.Cys441Tyr	missense	Exon 10 of 11	ENSP00000501534.1
	STS	ENST00000217961.5	TSL:1	c.1322G>A	p.Cys441Tyr	missense	Exon 9 of 10	ENSP00000217961.5
	STS	ENST00000666110.2		c.1322G>A	p.Cys441Tyr	missense	Exon 10 of 11	ENSP00000499472.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked ichthyosis with steryl-sulfatase deficiency Pathogenic:1

Aug 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.87		Gain of catalytic residue at C446 (P = 0.1194)
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.95
Mutation Taster		=5/95	disease causing (ClinVar)

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: rs137853166; hg19: chrX-7252107;