rs766760741

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_015884.4(MBTPS2):c.529A>C(p.Ile177Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000662 in 1,057,310 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000066 ( 0 hom. 1 hem. )

Consequence

MBTPS2
NM_015884.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.91

Publications

0 publications found

Variant links:

Genes affected

MBTPS2 (HGNC:15455): (membrane bound transcription factor peptidase, site 2) This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.[provided by RefSeq, Aug 2009]

MBTPS2 Gene-Disease associations (from GenCC):

IFAP syndrome 1, with or without BRESHECK syndrome
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
keratosis follicularis spinulosa decalvans
Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
Olmsted syndrome, X-linked
Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
osteogenesis imperfecta, type 19
Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
mutilating palmoplantar keratoderma with periorificial keratotic plaques
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
BRESEK syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
keratosis follicularis spinulosa decalvans, X-linked
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

MBTPS2 links:

ENSG00000308122 (HGNC:):

ENSG00000308122 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.267199).

BS2

High AC in GnomAdExome4 at 7 AD,XL gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBTPS2	NM_015884.4 link	c.529A>C	p.Ile177Leu	missense_variant	Exon 4 of 11	ENST00000379484.10	NP_056968.1	O43462

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MBTPS2	ENST00000379484.10 link	c.529A>C	p.Ile177Leu	missense_variant	Exon 4 of 11	1	NM_015884.4	ENSP00000368798.5	O43462
MBTPS2	ENST00000365779.2 link	c.529A>C	p.Ile177Leu	missense_variant	Exon 4 of 7	1		ENSP00000368796.1	B9ZVQ3
MBTPS2	ENST00000465888.1 link	n.628A>C		non_coding_transcript_exon_variant	Exon 4 of 6	2
ENSG00000308122	ENST00000831835.1 link	n.86+4521T>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183354

AF XY:

0.00

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:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000662

AC:

AN:

1057310

Hom.:

Cov.:

AF XY:

0.00000306

AC XY:

AN XY:

326538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25643

American (AMR)

AF:

0.00

AC:

AN:

35165

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19109

East Asian (EAS)

AF:

0.00

AC:

AN:

30065

South Asian (SAS)

AF:

0.0000376

AC:

AN:

53211

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4037

European-Non Finnish (NFE)

AF:

0.00000621

AC:

AN:

804861

Other (OTH)

AF:

0.00

AC:

AN:

44696

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

IFAP syndrome 1, with or without BRESHECK syndrome

Uncertain:1

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 177 of the MBTPS2 protein (p.Ile177Leu). This variant is present in population databases (rs766760741, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with MBTPS2-related conditions. ClinVar contains an entry for this variant (Variation ID: 522925). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MBTPS2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

0.0015

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;T

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

T;D

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-0.36

MutationAssessor

Benign

-0.080

N;.

PhyloP100

5.9

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.13

N;N

REVEL

Uncertain

0.30

Sift

Benign

0.16

T;T

Sift4G

Uncertain

0.034

D;D

Polyphen

0.062

B;B

Vest4

0.46

MutPred

0.27

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.71

MPC

0.67

ClinPred

0.82

GERP RS

2.8

Varity_R

0.19

gMVP

0.60

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over