X-21839750-C-CTGGTGG

Position:

• chrX-21839750-C-CTGGTGG

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The NM_015884.4(MBTPS2):​c.29_34dupTGGTGG​(p.Val10_Val11dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.000000928 in 1,077,163 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: MBTPS2 NM_015884.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.57

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_015884.4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.29_34dupTGGTGG	p.Val10_Val11dup	disruptive_inframe_insertion	1/11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.29_34dupTGGTGG	p.Val10_Val11dup	disruptive_inframe_insertion	1/11	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.29_34dupTGGTGG	p.Val10_Val11dup	disruptive_inframe_insertion	1/7	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.128_133dupTGGTGG		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077163 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 350855

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: 0.00000120

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In-frame insertion of 2 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 20, 2021	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant has not been reported in the literature in individuals affected with MBTPS2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.29_34dup, results in the insertion of 2 amino acid(s) of the MBTPS2 protein (p.Val10_Val11dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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-21857868;