NM_015884.4:c.119A>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_015884.4(MBTPS2):c.119A>G(p.Asn40Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,208,705 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., 11 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 14 hem. )

Consequence

MBTPS2
NM_015884.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.25

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 Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.030025095).

BP6

Variant X-21843213-A-G is Benign according to our data. Variant chrX-21843213-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 1575398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 11 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBTPS2	NM_015884.4 link	c.119A>G	p.Asn40Ser	missense_variant	Exon 2 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.119A>G	p.Asn40Ser	missense_variant	Exon 2 of 11	1	NM_015884.4	ENSP00000368798.5	O43462
MBTPS2	ENST00000365779.2 link	c.119A>G	p.Asn40Ser	missense_variant	Exon 2 of 7	1		ENSP00000368796.1	B9ZVQ3
MBTPS2	ENST00000465888.1 link	n.218A>G		non_coding_transcript_exon_variant	Exon 2 of 6	2

Frequencies

GnomAD3 genomes

AF:

0.000196

AC:

AN:

112188

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

AN XY:

34340

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00180

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000120

AC:

AN:

183511

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

67941

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000729

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:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000401

AC:

AN:

1096517

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

361897

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000286

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000196

AC:

AN:

112188

Hom.:

Cov.:

AF XY:

0.000320

AC XY:

AN XY:

34340

show subpopulations

Gnomad4 AFR

AF:

0.0000324

Gnomad4 AMR

AF:

0.00180

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000264

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MBTPS2: BP4, BS2 -

Aug 31, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MBTPS2-related disorder

Benign:1

Feb 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.32

DEOGEN2

Benign

0.036

T;T

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.084

MetaRNN

Benign

0.030

T;T

MetaSVM

Benign

-0.64

MutationAssessor

Benign

0.060

N;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.81

N;N

REVEL

Benign

0.25

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.035

MutPred

0.23

Gain of disorder (P = 0.0536);Gain of disorder (P = 0.0536);

MVP

0.59

MPC

0.50

ClinPred

0.026

GERP RS

4.4

Varity_R

0.15

gMVP

0.40

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

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