NM_015884.4:c.119A>C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_015884.4(MBTPS2):c.119A>C(p.Asn40Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,208,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N40S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000015 ( 0 hom. 6 hem. )

Consequence

MBTPS2
NM_015884.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.25

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):

keratosis follicularis spinulosa decalvans
Inheritance: AD, XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
IFAP syndrome 1, with or without BRESHECK syndrome
Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.11203742).

BS2

High AC in GnomAdExome4 at 16 AD,XL gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015884.4. 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
	MBTPS2	NM_015884.4	MANE Select	c.119A>C	p.Asn40Thr	missense	Exon 2 of 11	NP_056968.1	O43462

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MBTPS2	ENST00000379484.10	TSL:1 MANE Select	c.119A>C	p.Asn40Thr	missense	Exon 2 of 11	ENSP00000368798.5	O43462
MBTPS2	ENST00000365779.2	TSL:1	c.119A>C	p.Asn40Thr	missense	Exon 2 of 7	ENSP00000368796.1	B9ZVQ3
MBTPS2	ENST00000860794.1		c.203A>C	p.Asn68Thr	missense	Exon 3 of 12	ENSP00000530853.1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112188

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000375

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000545

AC:

AN:

183511

AF XY:

0.0000147

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:

0.0000146

AC:

AN:

1096518

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

361898

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26373

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19368

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54114

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

840565

Other (OTH)

AF:

0.00

AC:

AN:

46031

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

0.0000178

AC:

AN:

112188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30857

American (AMR)

AF:

0.00

AC:

AN:

10552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2655

East Asian (EAS)

AF:

0.00

AC:

AN:

3606

South Asian (SAS)

AF:

0.00

AC:

AN:

2706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6089

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000375

AC:

AN:

53291

Other (OTH)

AF:

0.00

AC:

AN:

1509

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

IFAP syndrome 1, with or without BRESHECK syndrome (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.061

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.68

M_CAP

Benign

0.065

MetaRNN

Benign

0.11

MetaSVM

Uncertain

-0.067

MutationAssessor

Benign

0.76

PhyloP100

1.3

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

REVEL

Benign

0.22

Sift

Benign

0.53

Sift4G

Benign

0.66

Polyphen

0.0030

Vest4

0.097

MutPred

0.27

Loss of loop (P = 0.0986)

MVP

0.65

MPC

0.65

ClinPred

0.066

GERP RS

4.4

Varity_R

0.24

gMVP

0.52

Mutation Taster

=80/20

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over