NM_015884.4:c.31G>A

Variant names:

• chrX-21839765-G-A
• NM_015884.4:c.31G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015884.4(MBTPS2):​c.31G>A​(p.Val11Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. V11G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• 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

ENSG00000304431 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31793168).

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.31G>A	p.Val11Met	missense	Exon 1 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.31G>A	p.Val11Met	missense	Exon 1 of 11	ENSP00000368798.5	O43462
	MBTPS2	ENST00000365779.2	TSL:1	c.31G>A	p.Val11Met	missense	Exon 1 of 7	ENSP00000368796.1	B9ZVQ3
	MBTPS2	ENST00000860794.1		c.31G>A	p.Val11Met	missense	Exon 1 of 12	ENSP00000530853.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1081634 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 353076

African (AFR) AF: 0.00 AC: 0 AN: 26190

American (AMR) AF: 0.00 AC: 0 AN: 32852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19013

East Asian (EAS) AF: 0.00 AC: 0 AN: 29572

South Asian (SAS) AF: 0.00 AC: 0 AN: 51762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39123

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4087

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833604

Other (OTH) AF: 0.00 AC: 0 AN: 45431

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.030	T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.34	N
PhyloP100		2.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.22
Sift	Benign	0.46	T
Sift4G	Benign	0.67	T
Polyphen		0.0020	B
Vest4		0.28
MutPred		0.22		Loss of catalytic residue at V11 (P = 0.0571)
MVP		0.64
MPC		0.64
ClinPred		0.56	D
GERP RS		3.2
PromoterAI		0.095	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.084
gMVP		0.61
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

hg19: chrX-21857883;