rs137853167

Variant names:

• chrX-7305109-C-T
• rs137853167
• NM_001320752.2:c.1007C>T

Variant summary

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

The NM_001320750.3(STS):​c.1043C>T​(p.Ser348Leu) variant causes a missense change. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S348S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: STS NM_001320750.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 4.95
• 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, 0.996
• PP5: Variant X-7305109-C-T is Pathogenic according to our data. Variant chrX-7305109-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10554.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001320750.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STS	NM_001320752.2	MANE Select	c.1007C>T	p.Ser336Leu	missense	Exon 8 of 11	NP_001307681.2
	STS	NM_001320750.3		c.1043C>T	p.Ser348Leu	missense	Exon 8 of 11	NP_001307679.1
	STS	NM_001320751.2		c.1043C>T	p.Ser348Leu	missense	Exon 9 of 12	NP_001307680.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STS	ENST00000674429.1	MANE Select	c.1007C>T	p.Ser336Leu	missense	Exon 8 of 11	ENSP00000501534.1
	STS	ENST00000217961.5	TSL:1	c.1007C>T	p.Ser336Leu	missense	Exon 7 of 10	ENSP00000217961.5
	STS	ENST00000666110.2		c.1007C>T	p.Ser336Leu	missense	Exon 8 of 11	ENSP00000499472.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
1	-	-	X-linked ichthyosis with steryl-sulfatase deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.66	D
BayesDel_noAF	Pathogenic	0.72
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		5.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.96		Loss of disorder (P = 0.0275)
MVP		0.99
MPC		0.89
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.91
gMVP		0.98
Mutation Taster		=23/77	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: rs137853167; hg19: chrX-7223150;