Genetic Variant STS:p.Ile3Phe (chrX-7253206-A-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001320752.2(STS):c.7A>T(p.Ile3Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000134 in 1,209,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 80 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.00014 ( 0 hom. 78 hem. )

Consequence

STS
NM_001320752.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.143

Publications

1 publications found

Variant links:

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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet

STS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005499363).

BP6

Variant X-7253206-A-T is Benign according to our data. Variant chrX-7253206-A-T is described in ClinVar as Benign. ClinVar VariationId is 2659916.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000538 (6/111467) while in subpopulation SAS AF = 0.00232 (6/2591). AF 95% confidence interval is 0.00101. There are 0 homozygotes in GnomAd4. There are 2 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 2 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STS	NM_001320752.2	MANE Select	c.7A>T	p.Ile3Phe	missense	Exon 3 of 11	NP_001307681.2	A0A590UJL0
STS	NM_001320750.3		c.43A>T	p.Ile15Phe	missense	Exon 3 of 11	NP_001307679.1
STS	NM_001320751.2		c.43A>T	p.Ile15Phe	missense	Exon 4 of 12	NP_001307680.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STS	ENST00000674429.1	MANE Select	c.7A>T	p.Ile3Phe	missense	Exon 3 of 11	ENSP00000501534.1	A0A590UJL0
STS	ENST00000217961.5	TSL:1	c.7A>T	p.Ile3Phe	missense	Exon 2 of 10	ENSP00000217961.5	A0A590UJL0
STS	ENST00000666110.2		c.7A>T	p.Ile3Phe	missense	Exon 3 of 11	ENSP00000499472.2	A0A590UJL0

Frequencies

GnomAD3 genomes

AF:

0.0000539

AC:

AN:

111415

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00231

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000246

AC:

AN:

182852

AF XY:

0.000238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.000142

AC:

156

AN:

1097753

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

363153

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26391

American (AMR)

AF:

0.00

AC:

AN:

35184

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19382

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00259

AC:

140

AN:

54114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40519

Middle Eastern (MID)

AF:

0.000486

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.00000356

AC:

AN:

841778

Other (OTH)

AF:

0.000239

AC:

AN:

46070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000538

AC:

AN:

111467

Hom.:

Cov.:

AF XY:

0.0000594

AC XY:

AN XY:

33671

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30704

American (AMR)

AF:

0.00

AC:

AN:

10449

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3521

South Asian (SAS)

AF:

0.00232

AC:

AN:

2591

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6069

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53076

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000102

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000239

AC:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.24

(source)

DANN

Benign

0.43

DEOGEN2

Uncertain

0.44

FATHMM_MKL

Benign

0.029

LIST_S2

Benign

0.42

M_CAP

Benign

0.017

MetaRNN

Benign

0.0055

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

0.060

PhyloP100

-0.14

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

REVEL

Benign

0.22

Sift

Benign

0.10

Sift4G

Benign

0.21

Polyphen

0.0010

Vest4

0.040

MutPred

0.51

Gain of loop (P = 0.0045)

MVP

0.23

MPC

0.57

ClinPred

0.0090

GERP RS

-3.6

Varity_R

0.094

gMVP

0.56

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over