rs122468178

chrX-21880921-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_015884.4(MBTPS2):c.1286G>A(p.Arg429His) 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.21

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-21880921-G-A is Pathogenic according to our data. Variant chrX-21880921-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11404.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-21880921-G-A is described in Lovd as [Pathogenic]. Variant chrX-21880921-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MBTPS2	NM_015884.4	c.1286G>A	p.Arg429His	missense_variant	10/11	ENST00000379484.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MBTPS2	ENST00000379484.10	c.1286G>A	p.Arg429His	missense_variant	10/11	1	NM_015884.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

IFAP syndrome 1, with or without BRESHECK syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant has been observed in multiple (>3) similarly affected unrelated individuals(PMID: 19361614, 23316014, PS4_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 19361614, 23316014, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.963, PP3_P). A missense variant is a common mechanism associated with IFAP syndrome with or without BRESHECK syndrome (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2019	Published functional studies demonstrate reduced enzymatic activity of the MBTPS2 protein, with variants such as R429H that are closer to the intramembranous domain being more detrimental than missense changes in the amino-terminal portion of the protein (Oeffner et al., 2009; Bornholdt et al; 2013); Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 19361614, 23316014, 22105905, 21179107, 27380894, 27663151, 26762237, 33258288) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2012	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.80		Loss of methylation at R429 (P = 0.0157);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs122468178; hg19: chrX-21899039;