rs2092904689

Variant names:

• chrX-21843269-C-T
• rs2092904689
• NM_015884.4:c.175C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015884.4(MBTPS2):​c.175C>T​(p.Arg59Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,097,379 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R59L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.76
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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.175C>T	p.Arg59Cys	missense	Exon 2 of 11	NP_056968.1	O43462

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBTPS2	ENST00000379484.10	TSL:1 MANE Select	c.175C>T	p.Arg59Cys	missense	Exon 2 of 11	ENSP00000368798.5	O43462
	MBTPS2	ENST00000365779.2	TSL:1	c.175C>T	p.Arg59Cys	missense	Exon 2 of 7	ENSP00000368796.1	B9ZVQ3
	MBTPS2	ENST00000860794.1		c.259C>T	p.Arg87Cys	missense	Exon 3 of 12	ENSP00000530853.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1097379 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 362753

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 54116

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841360

Other (OTH) AF: 0.0000434 AC: 2 AN: 46072

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Osteogenesis imperfecta, type 19 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.64
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.80		Loss of MoRF binding (P = 0.0115)
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.75
gMVP		0.89
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2092904689; hg19: chrX-21861387;