X-21843316-A-G

Position:

• chrX-21843316-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id is 95740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-21843316-A-G is described in Lovd as [Likely_pathogenic]. Variant chrX-21843316-A-G is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MBTPS2	NM_015884.4	c.222A>G	p.Gln74Gln	splice_region_variant, synonymous_variant	2/11	ENST00000379484.10	NP_056968.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MBTPS2	ENST00000379484.10	c.222A>G	p.Gln74Gln	splice_region_variant, synonymous_variant	2/11	1	NM_015884.4	ENSP00000368798.5
MBTPS2	ENST00000365779.2	c.222A>G	p.Gln74Gln	splice_region_variant, synonymous_variant	2/7	1		ENSP00000368796.1
MBTPS2	ENST00000465888.1	n.321A>G		splice_region_variant, non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 47283 AN: 110857 Hom.: 7323 Cov.: 23 AF XY: 0.426 AC XY: 14079 AN XY: 33081

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

GnomAD3 exomes AF: 0.429 AC: 78660 AN: 183179 Hom.: 11633 AF XY: 0.412 AC XY: 27859 AN XY: 67637

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 SAS exome AF: 0.315

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

Gnomad4 AFR exome AF: 0.466

Gnomad4 AMR exome AF: 0.552

Gnomad4 ASJ exome AF: 0.443

Gnomad4 EAS exome AF: 0.616

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.444

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.398

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

Gnomad4 AFR AF: 0.460

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.434

Gnomad4 EAS AF: 0.591

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.430

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.431

Alfa AF: 0.391 Hom.: 17446

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 09, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.2
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs3213451; hg19: chrX-21861434; COSMIC: COSV63411606; COSMIC: COSV63411606;