X-48523553-GAAAAA-GAAAA

Variant names:

• chrX-48523553-GA-G
• rs782437115
• NM_006579.3:c.-73-129delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006579.3(EBP):​c.-73-129delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0312 in 261,050 control chromosomes in the GnomAD database, including 15 homozygotes. There are 97 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (15 hom., 95 hem., cov: 19)
  • Exomes 𝑓: 0.032 (0 hom. 2 hem.)
• Consequence: EBP NM_006579.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.234
• Publications: 0 publications found

Genes affected

EBP (HGNC:3133): (EBP cholestenol delta-isomerase) The protein encoded by this gene is an integral membrane protein of the endoplasmic reticulum. It is a high affinity binding protein for the antiischemic phenylalkylamine Ca2+ antagonist [3H]emopamil and the photoaffinity label [3H]azidopamil. It is similar to sigma receptors and may be a member of a superfamily of high affinity drug-binding proteins in the endoplasmic reticulum of different tissues. This protein shares structural features with bacterial and eukaryontic drug transporting proteins. It has four putative transmembrane segments and contains two conserved glutamate residues which may be involved in the transport of cationic amphiphilics. Another prominent feature of this protein is its high content of aromatic amino acid residues (>23%) in its transmembrane segments. These aromatic amino acid residues have been suggested to be involved in the drug transport by the P-glycoprotein. Mutations in this gene cause Chondrodysplasia punctata 2 (CDPX2; also known as Conradi-Hunermann syndrome). [provided by RefSeq, Jul 2008]

EBP Gene-Disease associations (from GenCC):

• chondrodysplasia punctata 2, X-linked dominant

  Inheritance: XL Classification: DEFINITIVE Submitted by: Illumina
• MEND syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, ClinGen
• X-linked chondrodysplasia punctata 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P

ENSG00000286268 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-48523553-GA-G is Benign according to our data. Variant chrX-48523553-GA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1212535.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0694 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006579.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBP	NM_006579.3	MANE Select	c.-73-129delA		intron	N/A	NP_006570.1	Q15125

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EBP	ENST00000495186.6	TSL:1 MANE Select	c.-73-129delA		intron	N/A	ENSP00000417052.1	Q15125
	ENSG00000286268	ENST00000651615.1		c.-73-129delA		intron	N/A	ENSP00000498524.1	A0A494C0F3
	EBP	ENST00000882083.1		c.-202delA		5_prime_UTR	Exon 1 of 4	ENSP00000552142.1

Frequencies

GnomAD3 genomes AF: 0.0260 AC: 1208 AN: 46545 Hom.: 15 Cov.: 19

Gnomad AFR AF: 0.0734

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00454

Gnomad FIN AF: 0.00436

Gnomad MID AF: 0.0139

Gnomad NFE AF: 0.00992

Gnomad OTH AF: 0.0199

GnomAD4 exome AF: 0.0324 AC: 6948 AN: 214499 Hom.: 0 AF XY: 0.0000322 AC XY: 2 AN XY: 62119

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0596 AC: 384 AN: 6446

American (AMR) AF: 0.0274 AC: 284 AN: 10376

Ashkenazi Jewish (ASJ) AF: 0.0295 AC: 171 AN: 5797

East Asian (EAS) AF: 0.0430 AC: 518 AN: 12044

South Asian (SAS) AF: 0.00960 AC: 212 AN: 22077

European-Finnish (FIN) AF: 0.0347 AC: 404 AN: 11649

Middle Eastern (MID) AF: 0.0390 AC: 31 AN: 795

European-Non Finnish (NFE) AF: 0.0336 AC: 4470 AN: 133103

Other (OTH) AF: 0.0388 AC: 474 AN: 12212

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0260 AC: 1208 AN: 46551 Hom.: 15 Cov.: 19 AF XY: 0.0107 AC XY: 95 AN XY: 8903

African (AFR) AF: 0.0734 AC: 892 AN: 12145

American (AMR) AF: 0.0130 AC: 45 AN: 3458

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1378

East Asian (EAS) AF: 0.00 AC: 0 AN: 1258

South Asian (SAS) AF: 0.00343 AC: 3 AN: 874

European-Finnish (FIN) AF: 0.00436 AC: 5 AN: 1147

Middle Eastern (MID) AF: 0.0147 AC: 1 AN: 68

European-Non Finnish (NFE) AF: 0.00992 AC: 251 AN: 25306

Other (OTH) AF: 0.0196 AC: 11 AN: 562

Alfa AF: 0.000273 Hom.: 24

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs782437115; hg19: chrX-48381941;