rs587776867

Positions:

• chrX-21882618-A-G
• chrX-21882618-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Moderate

The NM_015884.4(MBTPS2):​c.1523A>G​(p.Asn508Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,932 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N508I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.81

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]

ACMG classification

Verdict is Pathogenic. Variant got 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-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 392629.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant X-21882618-A-G is Pathogenic according to our data. Variant chrX-21882618-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 29956.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-21882618-A-G is described in Lovd as [Pathogenic]. Variant chrX-21882618-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBTPS2	NM_015884.4	c.1523A>G	p.Asn508Ser	missense_variant	11/11	ENST00000379484.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBTPS2	ENST00000379484.10	c.1523A>G	p.Asn508Ser	missense_variant	11/11	1	NM_015884.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097932 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363292

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Keratosis follicularis spinulosa decalvans, X-linked Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2013

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2018

The N508S variant in the MBTPS2 gene has been reported previously in several generations of twounrelated families, in which hemizygous males presented with keratosis follicularis spinulosa decalvans(KFSD) and carrier females were asymptomatic or expressed mild symptoms (Aten et al., 2010). TheN508S variant also has been observed in a Chinese family with two siblings presenting with ichthyosisfollicularis, alopecia and photophobia (IFAP) and a carrier mother with dry skin and ichthyosiformscaling and atrophoderma following lines of Blaschko (Ding et al., 2010). The N508S variant was notobserved in approximately 6500 individuals of European and African American ancestry in theNHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Although N508S is a conservative amino acid substitution, which is not likely to impact secondaryprotein structure, this substitution occurs at a position that is conserved across species. Functional studies using in vitro expression demonstrated that the proteolytic activity of the MBTPS2 protein isabolished in the presence of the N508S variant (Aten et al., 2010). Therefore, we interpret the N508Svariant as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.36		Loss of sheet (P = 0.0817);
MVP		0.94
MPC		1.5
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.72
gMVP		0.99

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

LitVar

Other links and lift over

dbSNP: rs587776867; hg19: chrX-21900736;