9-127826640-CG-C

Variant names:

• chr9-127826640-CG-C
• rs1554810510
• NM_001114753.3:c.392delC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.392delC​(p.Pro131ArgfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 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. P131P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.0560
• Publications: 1 publications found

Genes affected

ENG (HGNC:3349): (endoglin) This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

ENG Gene-Disease associations (from GenCC):

• telangiectasia, hereditary hemorrhagic, type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
• hereditary hemorrhagic telangiectasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• juvenile polyposis syndrome

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 9-127826640-CG-C is Pathogenic according to our data. Variant chr9-127826640-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 458347.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.392delC	p.Pro131ArgfsTer32	frameshift_variant	Exon 4 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.392delC	p.Pro131ArgfsTer32	frameshift_variant	Exon 4 of 14		NP_000109.1
ENG	NM_001406715.1	c.392delC	p.Pro131ArgfsTer32	frameshift_variant	Exon 4 of 8		NP_001393644.1
ENG	NM_001278138.2	c.-155delC		5_prime_UTR_variant	Exon 4 of 15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.392delC	p.Pro131ArgfsTer32	frameshift_variant	Exon 4 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112004

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Sep 13, 2019

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392del (p.Pro131ArgfsTer32) variant identified in the ENG gene is the deletion of a single nucleotide resulting in the frameshift of the protein at amino acid 131/659 (coding exon 4/15), which is predicted to lead to the premature termination of the protein approximately 32 amino acids downstream of the variant. This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. This variant is classified as Pathogenic in ClinVar (VarID:458347), and has been identified in two individuals in the literature with hereditary haemorrhagic telangiectasia [PMID: 16542389; PMID: 30251589]. This variant was identified in a proband submitted for clinical testing, and found to be inherited from an affected parent. The c.392del (p.Pro131ArgfsTer32) variant is reported here as Pathogenic. -

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Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Nov 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 458347). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individuals with epistaxis, telangiectasias and gastrointestinal bleeding (PMID: 16542389). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Pro131Argfs*32) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). -

Cardiovascular phenotype Pathogenic:1

Jul 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.392delC pathogenic mutation, located in coding exon 4 of the ENG gene, results from a deletion of one nucleotide at nucleotide position 392, causing a translational frameshift with a predicted alternate stop codon (p.P131Rfs*32). This variant was reported in individuals with features consistent with hereditary hemorrhagic telangiectasia (Wehner LE et al. Clin Genet, 2006 Mar;69:239-45; Karlsson T et al. Ups J Med Sci, 2018 Sep;123:153-157; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.056
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554810510; hg19: chr9-130588919;