chrX-21839765-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/20 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)
  • 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

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 1 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 11	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.31G>A	p.Val11Met	missense_variant	Exon 1 of 7	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.130G>A		non_coding_transcript_exon_variant	Exon 1 of 6	2

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

Gnomad4 AFR exome AF: 0.00

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 11 of the MBTPS2 protein (p.Val11Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MBTPS2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

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;T
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	-0.34	N;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.22
Sift	Benign	0.46	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0020	B;B
Vest4		0.28
MutPred		0.22		Loss of catalytic residue at V11 (P = 0.0571);Loss of catalytic residue at V11 (P = 0.0571);
MVP		0.64
MPC		0.64
ClinPred		0.56	D
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.084
gMVP		0.61

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-21857883;