X-21851599-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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

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=0.15159622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.529A>G	p.Ile177Val	missense_variant	Exon 4 of 11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.529A>G	p.Ile177Val	missense_variant	Exon 4 of 11	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.529A>G	p.Ile177Val	missense_variant	Exon 4 of 7	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.628A>G		non_coding_transcript_exon_variant	Exon 4 of 6	2

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

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: 0.00000124

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Benign	-0.90	N;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0070	B;B
Vest4		0.19
MutPred		0.31		Gain of sheet (P = 0.0344);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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-21869717;