rs1443187318

Positions:

• chr7-44108060-T-TA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The ENST00000223357.8(AEBP1):​c.917dup​(p.Tyr306Ter) variant causes a stop gained, frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,451,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y306Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: AEBP1 ENST00000223357.8 stop_gained, frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.903

Genes affected

AEBP1 (HGNC:303): (AE binding protein 1) This gene encodes a member of carboxypeptidase A protein family. The encoded protein may function as a transcriptional repressor and play a role in adipogenesis and smooth muscle cell differentiation. Studies in mice suggest that this gene functions in wound healing and abdominal wall development. Overexpression of this gene is associated with glioblastoma. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-44108060-T-TA is Pathogenic according to our data. Variant chr7-44108060-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 545699.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AEBP1	NM_001129.5	c.917dup	p.Tyr306Ter	stop_gained, frameshift_variant	6/21	ENST00000223357.8	NP_001120.3
AEBP1	XM_011515162.2	c.917dup	p.Tyr306Ter	stop_gained, frameshift_variant	6/20		XP_011513464.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AEBP1	ENST00000223357.8	c.917dup	p.Tyr306Ter	stop_gained, frameshift_variant	6/21	1	NM_001129.5	ENSP00000223357	P1
AEBP1	ENST00000455443.5	c.594dup	p.Tyr199Ter	stop_gained, frameshift_variant	4/6	5		ENSP00000411277

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000128 AC: 3 AN: 234350 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126998

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000287

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1451114 Hom.: 0 Cov.: 35 AF XY: 0.00000139 AC XY: 1 AN XY: 720990

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: 0.00000451

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic-like, 2 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	May 31, 2018	The homozygous c.917dup variant in exon 6 of AEBP1 gene was identified in two Greek siblings with an Ehlers-Danlos Syndrome associated connective tissue disorder. This variant is predicted to directly cause a premature termination codon (p.Tyr306*) and is only present in 2/229,558 alleles in gnomAD. Sanger sequencing of cDNA showed a predominant expression of the normal allele in the carrier mother. This indicates a nonsense-mediated decay of c.917dup allele, suggesting a null variant in the affected individuals. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1443187318; hg19: chr7-44147659;