chr9-127829686-C-T

Variant names:

• chr9-127829686-C-T
• rs886039505
• NM_001114753.3:c.360+1G>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.360+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.53

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07132018 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127829686-C-T is Pathogenic according to our data. Variant chr9-127829686-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 265370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829686-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.360+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.360+1G>A		splice_donor_variant, intron_variant	Intron 3 of 13		NP_000109.1
ENG	NM_001278138.2	c.-187+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14		NP_001265067.1
ENG	NM_001406715.1	c.360+1G>A		splice_donor_variant, intron_variant	Intron 3 of 7		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.360+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.360+1G>A		splice_donor_variant, intron_variant	Intron 3 of 13	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-187+1G>A		splice_donor_variant, intron_variant	Intron 3 of 14	2		ENSP00000479015.1
ENG	ENST00000462196.1	n.118+1G>A		splice_donor_variant, intron_variant	Intron 1 of 3	3		ENSP00000519251.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:4

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1+PM2+PP4 -

Feb 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ENG c.360+1G>A variant (rs886039505) is reported in the literature in multiple individuals and families with hereditary hemorrhagic telangiectasia (ENG HHT database, Heimdal 2016, Kim 2011, McDonald 2011, Nishida 2012, Pece 1997, Sadick 2009, Schulte 2005). This variant is reported in ClinVar (Variation ID: 265370) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Functional analysis shows that this variant disrupts the canonical splice donor site in the 5’ end of intron 3 and leads to skipping of exon 3 (Pece 1997). Based on the above information, this variant is considered pathogenic. References: ENG HHT database: http://arup.utah.edu/database/ENG/ENG_display.php Heimdal K et al. Mutation analysis in Norwegian families with hereditary hemorrhagic telangiectasia: founder mutations in ACVRL1. Clin Genet. 2016 Feb;89(2):182-6. PMID: 25970827. Kim M et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011; 12: 130. PMID: 21967607. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. PMID: 21158752. Nishida T et al. Brain Arteriovenous Malformations associated with Hereditary Hemorrhagic Telangiectasia: Gene-Phenotype Correlations. Am J Med Genet A. 2012 Nov; 0(11): 2829–2834. PMID: 22991266. Pece N et al. Mutant endoglin in hereditary hemorrhagic telangiectasia type 1 is transiently expressed intracellularly and is not a dominant negative. J Clin Invest. 1997 Nov 15;100(10):2568-79. PMID: 9366572. Sadick H et al. Mutation analysis of "Endoglin" and "Activin receptor-like kinase" genes in German patients with hereditary hemorrhagic telangiectasia and the value of rapid genotyping using an allele-specific PCR-technique. BMC Med Genet. 2009; 10: 53. PMID: 19508727. Schulte C et al. High frequency of ENG and ALK1/ACVRL1 mutations in German HHT patients. Hum Mutat. 2005 Jun;25(6):595. PMID: 15880681. -

not provided Pathogenic:3

Apr 14, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in multiple unrelated patients with HHT across various ethnic backgrounds (Pece et al., 1997; Cymerman et al., 2003; Letteboer et al., 2005; Schulte et al., 2005; Bayrak-Toydemir et al., 2006; Bossler et al., 2006; Olivieri et al., 2007; Kim et al., 2011; Nishida et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant expected to result in aberrant splicing; Functional studies demonstrate that c.360+1 G>A leads to an in-frame skip of exon 3 and reduced cell surface endoglin protein, which the authors propose as transient intracellular expression likely due to protein degradation (Pece et al., 1997); This variant is associated with the following publications: (PMID: 23801935, 34872578, 25525159, 15879500, 15517393, 23805858, 16470787, 15880681, 16752392, 17786384, 12673790, 10625079, 15266205, 19508727, 31589614, 34530633, 31455059, 32300199, 33677851, 31400083, 30685840, 33919892, 34501220, 21158752, 25970827, 22991266, 16754821, 21967607, 9366572) -

Aug 11, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 10, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PM2, PS2, PS3_moderate, PS4_moderate, PVS1 -

Hereditary hemorrhagic telangiectasia Pathogenic:2

Mar 30, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change in ENG occurs within the canonical splice donor site (+ 1) of intron 3. It is predicted to cause skipping of biologically relevant-exon 3/15, resulting in an in-frame deletion (removes amino acids 74-120) that escapes nonsense-mediated decay and removes a critical region of the protein. This prediction is confirmed by RT-PCR of cDNA from patient cells and demonstrated that the variant impacts splicing by causing exon 3 skipping and leading to loss of endoglin expression on the cell surface (PMID: 13043988). This variant is absent from gnomAD v2.1 and v3.1. This variant has been reported in multiple families meeting a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT), and segregates with disease in affected family members (PMID: 9366572, 12673790, 21967607). This variant has been identified as a de novo occurrence with confirmed parental relationships in one individual with a clinical diagnosis of HHT (PMID: 12673790). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1_Strong, PS2, PP1_Strong, PM2_Supporting. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the ENG gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 9366572, 15880681, 19508727, 21158752, 21967607, 22991266, 25970827). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265370). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects ENG function (PMID: 9366572). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Feb 29, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.360+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 3 of the ENG gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay. The exact functional effect of the missing amino acids is unknown; however, the impacted region is critical for protein function (Ambry internal data). This mutation has been identified in multiple individuals and families with hereditary hemorrhagic telangiectasia (HHT) and has been reported to result in in-frame skipping of exon 3 (Pece N et al. J. Clin. Invest., 1997 Nov;100:2568-79; Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Schulte C et al. Hum. Mutat., 2005 Jun;25:595; Bayrak-Toydemir P et al. Am. J. Med. Genet. A, 2006 Mar;140:463-70; Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Kim MJ et al. BMC Med. Genet., 2011 Oct;12:130; Heimdal K et al. Clin. Genet., 2016 Feb;89:182-6). In one family, this mutation was identified in one individual with epistaxis and pulmonary arteriovenous malformations (PAVMs) and in a second individual with epistaxis, PAVMs, telangiectasias, and hepatic involvement; mature ENG levels in activated monocytes or umbilical vein endothelial cells from these two individuals was decreased compared to wild type (Cymerman U et al. Hum. Mutat., 2003 May;21:482-92). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	0.87
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886039505; hg19: chr9-130591965; COSMIC: COSV61227348; COSMIC: COSV61227348;