rs199974151

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_015884.4(MBTPS2):c.290C>T(p.Thr97Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,209,409 control chromosomes in the GnomAD database, including 1 homozygotes. There are 22 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T97T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000038 ( 1 hom. 19 hem. )

Consequence

MBTPS2
NM_015884.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 7.42

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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

BP6

Variant X-21845236-C-T is Benign according to our data. Variant chrX-21845236-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521430.

BS2

High AC in GnomAd4 at 7 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBTPS2	NM_015884.4	MANE Select	c.290C>T	p.Thr97Met	missense	Exon 3 of 11	NP_056968.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MBTPS2	ENST00000379484.10	TSL:1 MANE Select	c.290C>T	p.Thr97Met	missense	Exon 3 of 11	ENSP00000368798.5
MBTPS2	ENST00000365779.2	TSL:1	c.290C>T	p.Thr97Met	missense	Exon 3 of 7	ENSP00000368796.1
MBTPS2	ENST00000465888.1	TSL:2	n.389C>T		non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes

AF:

0.0000628

AC:

AN:

111551

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000496

AC:

AN:

181549

AF XY:

0.0000594

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000383

AC:

AN:

1097858

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30194

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40522

Middle Eastern (MID)

AF:

0.000726

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

841811

Other (OTH)

AF:

0.0000651

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.0000628

AC:

AN:

111551

Hom.:

Cov.:

AF XY:

0.0000889

AC XY:

AN XY:

33741

show subpopulations

African (AFR)

AF:

0.0000326

AC:

AN:

30711

American (AMR)

AF:

0.00

AC:

AN:

10435

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2646

East Asian (EAS)

AF:

0.00

AC:

AN:

3576

South Asian (SAS)

AF:

0.00

AC:

AN:

2687

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5917

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53150

Other (OTH)

AF:

0.00

AC:

AN:

1506

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.0000867

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 29, 2016

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

Jun 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.86

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-1.9

REVEL

Pathogenic

0.76

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.89

MVP

0.95

MPC

1.1

ClinPred

0.39

GERP RS

5.8

Varity_R

0.11

gMVP

0.85

Mutation Taster

=79/21

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over