Variant rs766760741 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBTPS2	NM_015884.4 linkuse as main transcript	c.529A>C	p.Ile177Leu	missense_variant	4/11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
MBTPS2	ENST00000379484.10 linkuse as main transcript	c.529A>C	p.Ile177Leu	missense_variant	4/11	1	NM_015884.4	ENSP00000368798	P1
MBTPS2	ENST00000365779.2 linkuse as main transcript	c.529A>C	p.Ile177Leu	missense_variant	4/7	1		ENSP00000368796
MBTPS2	ENST00000465888.1 linkuse as main transcript	n.628A>C		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183354

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67820

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000376

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000621

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 27, 2023

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. 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. ClinVar contains an entry for this variant (Variation ID: 522925). This variant has not been reported in the literature in individuals affected with MBTPS2-related conditions. This variant is present in population databases (rs766760741, gnomAD 0.001%). 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). -

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

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;.

MutationTaster

Benign

0.74

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over