X-21843316-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_015884.4(MBTPS2):c.222A>G(p.Gln74Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,207,606 control chromosomes in the GnomAD database, including 64,966 homozygotes. There are 154,278 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 7325 hom., 14123 hem., cov: 23)

Exomes 𝑓: 0.39 ( 57641 hom. 140155 hem. )

Consequence

MBTPS2
NM_015884.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0007513

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.129

Publications

23 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), ClinGen, Orphanet, Ambry Genetics
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: G2P, Ambry Genetics
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant X-21843316-A-G is Benign according to our data. Variant chrX-21843316-A-G is described in ClinVar as Benign. ClinVar VariationId is 95740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.129 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

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.222A>G	p.Gln74Gln	splice_region synonymous	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.222A>G	p.Gln74Gln	splice_region synonymous	Exon 2 of 11	ENSP00000368798.5	O43462
MBTPS2	ENST00000365779.2	TSL:1	c.222A>G	p.Gln74Gln	splice_region synonymous	Exon 2 of 7	ENSP00000368796.1	B9ZVQ3
MBTPS2	ENST00000860794.1		c.306A>G	p.Gln102Gln	splice_region synonymous	Exon 3 of 12	ENSP00000530853.1

Frequencies

GnomAD3 genomes

AF:

0.427

AC:

47283

AN:

110857

Hom.:

7323

Cov.:

show subpopulations

Gnomad AFR

AF:

0.460

Gnomad AMI

AF:

0.709

Gnomad AMR

AF:

0.544

Gnomad ASJ

AF:

0.434

Gnomad EAS

AF:

0.590

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.430

Gnomad MID

AF:

0.336

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.432

GnomAD2 exomes

AF:

0.429

AC:

78660

AN:

183179

AF XY:

0.412

show subpopulations

Gnomad AFR exome

AF:

0.476

Gnomad AMR exome

AF:

0.549

Gnomad ASJ exome

AF:

0.449

Gnomad EAS exome

AF:

0.600

Gnomad FIN exome

AF:

0.446

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.417

GnomAD4 exome

AF:

0.390

AC:

427226

AN:

1096694

Hom.:

57641

Cov.:

AF XY:

0.387

AC XY:

140155

AN XY:

362392

show subpopulations

African (AFR)

AF:

0.466

AC:

12293

AN:

26371

American (AMR)

AF:

0.552

AC:

19430

AN:

35190

Ashkenazi Jewish (ASJ)

AF:

0.443

AC:

8573

AN:

19368

East Asian (EAS)

AF:

0.616

AC:

18592

AN:

30189

South Asian (SAS)

AF:

0.320

AC:

17300

AN:

54114

European-Finnish (FIN)

AF:

0.444

AC:

17997

AN:

40521

Middle Eastern (MID)

AF:

0.334

AC:

1378

AN:

4131

European-Non Finnish (NFE)

AF:

0.373

AC:

313334

AN:

840765

Other (OTH)

AF:

0.398

AC:

18329

AN:

46045

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

8687

17374

26062

34749

43436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10926

21852

32778

43704

54630

<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:

0.427

AC:

47329

AN:

110912

Hom.:

7325

Cov.:

AF XY:

0.426

AC XY:

14123

AN XY:

33146

show subpopulations

African (AFR)

AF:

0.460

AC:

14069

AN:

30554

American (AMR)

AF:

0.545

AC:

5676

AN:

10406

Ashkenazi Jewish (ASJ)

AF:

0.434

AC:

1142

AN:

2631

East Asian (EAS)

AF:

0.591

AC:

2065

AN:

3497

South Asian (SAS)

AF:

0.319

AC:

849

AN:

2664

European-Finnish (FIN)

AF:

0.430

AC:

2516

AN:

5855

Middle Eastern (MID)

AF:

0.313

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.375

AC:

19820

AN:

52911

Other (OTH)

AF:

0.431

AC:

650

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

984

1968

2953

3937

4921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

454

908

1362

1816

2270

<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:

0.398

Hom.:

23198

Bravo

AF:

0.443

EpiCase

AF:

0.387

EpiControl

AF:

0.379

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.2

(source)

DANN

Benign

0.67

PhyloP100

-0.13

Mutation Taster

=43/57

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00075

dbscSNV1_RF

Benign

0.028

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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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