X-21839801-G-C

Position:

• chrX-21839801-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015884.4(MBTPS2):​c.67G>C​(p.Val23Leu) 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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.57

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.089696795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.67G>C	p.Val23Leu	missense_variant	1/11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.67G>C	p.Val23Leu	missense_variant	1/11	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.67G>C	p.Val23Leu	missense_variant	1/7	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.166G>C		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

MBTPS2: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.024	T;T
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.090	T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	-0.64	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.13	N;N
REVEL	Benign	0.23
Sift	Benign	0.88	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.16
MutPred		0.49		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.47
MPC		0.63
ClinPred		0.096	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.087
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21857919;