X-21843316-A-G

Variant names:

• chrX-21843316-A-G
• rs3213451
• NM_015884.4:c.222A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015884.4(MBTPS2):​c.222A>G​(p.Gln74Gln) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,207,606 control chromosomes in the GnomAD database, including 64,966 homozygotes. There are 154,278 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (7325 hom., 14123 hem., cov: 23)
  • Exomes 𝑓: 0.39 (57641 hom. 140155 hem.)
• Consequence: MBTPS2 NM_015884.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0007513
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.129
• Publications: 23 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-21843316-A-G is Benign according to our data. Variant chrX-21843316-A-G is described in ClinVar as Benign. ClinVar VariationId is 95740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.129 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.569 is higher than 0.05.

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.222A>G	p.Gln74Gln	splice_region synonymous	Exon 2 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.222A>G	p.Gln74Gln	splice_region synonymous	Exon 2 of 11	ENSP00000368798.5
	MBTPS2	ENST00000365779.2	TSL:1	c.222A>G	p.Gln74Gln	splice_region synonymous	Exon 2 of 7	ENSP00000368796.1
	MBTPS2	ENST00000465888.1	TSL:2	n.321A>G		splice_region non_coding_transcript_exon	Exon 2 of 6

Frequencies

GnomAD3 genomes AF: 0.427 AC: 47283 AN: 110857 Hom.: 7323 Cov.: 23

Gnomad AFR AF: 0.460

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.544

Gnomad ASJ AF: 0.434

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.336

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.429 AC: 78660 AN: 183179 AF XY: 0.412

Gnomad AFR exome AF: 0.476

Gnomad AMR exome AF: 0.549

Gnomad ASJ exome AF: 0.449

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.375

Gnomad OTH exome AF: 0.417

GnomAD4 exome AF: 0.390 AC: 427226 AN: 1096694 Hom.: 57641 Cov.: 32 AF XY: 0.387 AC XY: 140155 AN XY: 362392

African (AFR) AF: 0.466 AC: 12293 AN: 26371

American (AMR) AF: 0.552 AC: 19430 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 8573 AN: 19368

East Asian (EAS) AF: 0.616 AC: 18592 AN: 30189

South Asian (SAS) AF: 0.320 AC: 17300 AN: 54114

European-Finnish (FIN) AF: 0.444 AC: 17997 AN: 40521

Middle Eastern (MID) AF: 0.334 AC: 1378 AN: 4131

European-Non Finnish (NFE) AF: 0.373 AC: 313334 AN: 840765

Other (OTH) AF: 0.398 AC: 18329 AN: 46045

GnomAD4 genome AF: 0.427 AC: 47329 AN: 110912 Hom.: 7325 Cov.: 23 AF XY: 0.426 AC XY: 14123 AN XY: 33146

African (AFR) AF: 0.460 AC: 14069 AN: 30554

American (AMR) AF: 0.545 AC: 5676 AN: 10406

Ashkenazi Jewish (ASJ) AF: 0.434 AC: 1142 AN: 2631

East Asian (EAS) AF: 0.591 AC: 2065 AN: 3497

South Asian (SAS) AF: 0.319 AC: 849 AN: 2664

European-Finnish (FIN) AF: 0.430 AC: 2516 AN: 5855

Middle Eastern (MID) AF: 0.313 AC: 68 AN: 217

European-Non Finnish (NFE) AF: 0.375 AC: 19820 AN: 52911

Other (OTH) AF: 0.431 AC: 650 AN: 1508

Alfa AF: 0.398 Hom.: 23198

Bravo AF: 0.443

EpiCase AF: 0.387

EpiControl AF: 0.379

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jul 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.67
PhyloP100		-0.13
Mutation Taster		=43/57	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00075
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.080		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: rs3213451; hg19: chrX-21861434; COSMIC: COSV63411606; COSMIC: COSV63411606;