X-21882618-A-T

Variant names:

• chrX-21882618-A-T
• rs587776867
• NM_015884.4:c.1523A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_015884.4(MBTPS2):​c.1523A>T​(p.Asn508Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N508T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.81
• Publications: 13 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):

• 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_015884.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-21882618-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 29956.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901
• PP5: Variant X-21882618-A-T is Pathogenic according to our data. Variant chrX-21882618-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 392629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.1523A>T	p.Asn508Ile	missense_variant	Exon 11 of 11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.1523A>T	p.Asn508Ile	missense_variant	Exon 11 of 11	1	NM_015884.4	ENSP00000368798.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jan 16, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The N508I variant in the MBTPS2 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However, a different missense alteration affecting the same codon (N508S) has been previously reported as a pathogenic variant in several generations of two unrelated families, in which hemizygous males presented with keratosis follicularis spinulosa decalvans (KFSD) and carrier females were asymptomatic or expressed mild symptoms; the N508S variant also has been observed in a Chinese family with two siblings presenting with ichthyosis follicularis, alopecia and photophobia (IFAP) and a carrier mother with dry skin and ichthyosiform scaling and atrophoderma following lines of Blaschko (Aten et al., 2010; Ding et al., 2010). The N508I variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N508I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the information available, the N508I variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.38		Gain of helix (P = 0.0128);
MVP		0.94
MPC		1.8
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.92
gMVP		1.0
Mutation Taster		=12/88	disease causing (ClinVar)

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

dbSNP: rs587776867; hg19: chrX-21900736;