X-21851599-A-G

Variant names:

• chrX-21851599-A-G
• rs766760741
• NM_015884.4:c.529A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015884.4(MBTPS2):​c.529A>G​(p.Ile177Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000946 in 1,057,307 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I177L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: MBTPS2 NM_015884.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.91
• Publications: 0 publications found

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]

MBTPS2 Gene-Disease associations (from GenCC):

• IFAP syndrome 1, with or without BRESHECK syndrome

  Inheritance: XL, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet
• keratosis follicularis spinulosa decalvans

  Inheritance: XL, AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• Olmsted syndrome, X-linked

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P
• osteogenesis imperfecta, type 19

  Inheritance: XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• BRESEK syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• keratosis follicularis spinulosa decalvans, X-linked

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000308122 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15159622).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015884.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBTPS2	NM_015884.4	MANE Select	c.529A>G	p.Ile177Val	missense	Exon 4 of 11	NP_056968.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MBTPS2	ENST00000379484.10	TSL:1 MANE Select	c.529A>G	p.Ile177Val	missense	Exon 4 of 11	ENSP00000368798.5
	MBTPS2	ENST00000365779.2	TSL:1	c.529A>G	p.Ile177Val	missense	Exon 4 of 7	ENSP00000368796.1
	MBTPS2	ENST00000465888.1	TSL:2	n.628A>G		non_coding_transcript_exon	Exon 4 of 6

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.46e-7 AC: 1 AN: 1057307 Hom.: 0 Cov.: 26 AF XY: 0.00000306 AC XY: 1 AN XY: 326535

African (AFR) AF: 0.00 AC: 0 AN: 25643

American (AMR) AF: 0.00 AC: 0 AN: 35165

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19109

East Asian (EAS) AF: 0.00 AC: 0 AN: 30065

South Asian (SAS) AF: 0.00 AC: 0 AN: 53211

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40523

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4037

European-Non Finnish (NFE) AF: 0.00000124 AC: 1 AN: 804858

Other (OTH) AF: 0.00 AC: 0 AN: 44696

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Benign	0.30	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.90	N
PhyloP100		5.9
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.27
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0070	B
Vest4		0.19
MutPred		0.31		Gain of sheet (P = 0.0344)
MVP		0.51
MPC		0.55
ClinPred		0.80	D
GERP RS		2.8
Varity_R		0.066
gMVP		0.26
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766760741; hg19: chrX-21869717;