X-7325357-G-T

Variant names:

• chrX-7325357-G-T
• rs137853168
• NM_001320752.2:c.1100G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PM1 PM5 PP3_Strong BS2

The NM_001320752.2(STS):​c.1100G>T​(p.Trp367Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000455 in 1,097,939 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W367R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 4 hem.)
• Consequence: STS NM_001320752.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• Publications: 0 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001320752.2
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-7325356-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10552.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STS	NM_001320752.2	MANE Select	c.1100G>T	p.Trp367Leu	missense	Exon 9 of 11	NP_001307681.2	A0A590UJL0
	STS	NM_001320750.3		c.1136G>T	p.Trp379Leu	missense	Exon 9 of 11	NP_001307679.1
	STS	NM_001320751.2		c.1136G>T	p.Trp379Leu	missense	Exon 10 of 12	NP_001307680.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STS	ENST00000674429.1	MANE Select	c.1100G>T	p.Trp367Leu	missense	Exon 9 of 11	ENSP00000501534.1	A0A590UJL0
	STS	ENST00000217961.5	TSL:1	c.1100G>T	p.Trp367Leu	missense	Exon 8 of 10	ENSP00000217961.5	A0A590UJL0
	STS	ENST00000666110.2		c.1100G>T	p.Trp367Leu	missense	Exon 9 of 11	ENSP00000499472.2	A0A590UJL0

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000455 AC: 5 AN: 1097939 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 363333

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30180

South Asian (SAS) AF: 0.00 AC: 0 AN: 54131

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40515

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000475 AC: 4 AN: 841919

Other (OTH) AF: 0.0000217 AC: 1 AN: 46081

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.91	D
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.83
Sift	Benign	0.033	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.83		Loss of MoRF binding (P = 0.0286)
MVP		0.92
MPC		1.2
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.91
gMVP		0.87
Mutation Taster		=26/74	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: rs137853168; hg19: chrX-7243398;