X-48523553-GAAAAA-GAA

Variant names:

• chrX-48523553-GAAA-G
• rs782437115
• NM_006579.3:c.-73-131_-73-129delAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_006579.3(EBP):​c.-73-131_-73-129delAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00072 in 270,883 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000064 (0 hom., 0 hem., cov: 19)
  • Exomes 𝑓: 0.00086 (0 hom. 0 hem.)
• Consequence: EBP NM_006579.3 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000644 (3/46573) while in subpopulation AMR AF = 0.000289 (1/3460). AF 95% confidence interval is 0.0000131. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

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.-73-131_-73-129delAAA		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.-73-131_-73-129delAAA		intron	N/A	ENSP00000417052.1	Q15125
	ENSG00000286268	ENST00000651615.1		c.-73-131_-73-129delAAA		intron	N/A	ENSP00000498524.1	A0A494C0F3
	EBP	ENST00000882083.1		c.-204_-202delAAA		5_prime_UTR	Exon 1 of 4	ENSP00000552142.1

Frequencies

GnomAD3 genomes AF: 0.0000644 AC: 3 AN: 46567 Hom.: 0 Cov.: 19

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000289

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000790

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000856 AC: 192 AN: 224310 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 71308

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

African (AFR) AF: 0.000893 AC: 6 AN: 6716

American (AMR) AF: 0.00111 AC: 12 AN: 10764

Ashkenazi Jewish (ASJ) AF: 0.00148 AC: 9 AN: 6061

East Asian (EAS) AF: 0.000635 AC: 8 AN: 12595

South Asian (SAS) AF: 0.000127 AC: 3 AN: 23549

European-Finnish (FIN) AF: 0.000906 AC: 11 AN: 12140

Middle Eastern (MID) AF: 0.00121 AC: 1 AN: 828

European-Non Finnish (NFE) AF: 0.000921 AC: 128 AN: 138924

Other (OTH) AF: 0.00110 AC: 14 AN: 12733

⚠️ 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: 0.0000644 AC: 3 AN: 46573 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 8911

African (AFR) AF: 0.00 AC: 0 AN: 12158

American (AMR) AF: 0.000289 AC: 1 AN: 3460

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1149

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 68

European-Non Finnish (NFE) AF: 0.0000790 AC: 2 AN: 25311

Other (OTH) AF: 0.00 AC: 0 AN: 562

Alfa AF: 0.00 Hom.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.23

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;