rs863223542

Positions:

• chr9-127818715-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_Moderate PM2 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):​c.1428+1G>A variant causes a splice donor change. 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENG NM_001114753.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 4.30

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.05867476 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-127818715-C-T is Pathogenic according to our data. Variant chr9-127818715-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 213216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1428+1G>A		splice_donor_variant		ENST00000373203.9
LOC102723566	NR_136302.1	n.1568+4C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1428+1G>A		splice_donor_variant
ENG	NM_001278138.2	c.882+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1428+1G>A		splice_donor_variant		1	NM_001114753.3	P2
	ENST00000439298.5	n.1568+4C>T		splice_donor_region_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ENG NM_000118.3 exon 11 c.1428+1G>A: This variant has been reported in the literature in 3 individuals with hereditary hemorrhagic telangiectasia (HHT) (McDonald 2011 PMID:21158752, Nishida 2012 PMID:22991266). This variant is not present in large control databases but is present in ClinVar (Variation ID:213216). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Abdalla 2006 PMID:15879500, Wooderchak 2010 PMID:20412114). In summary, this variant is classified as pathogenic based on the data above. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2020	The ENG c.1428+1G>A variant (rs863223542) has been reported in the literature individuals affected with HHT (Nishida 2012, McDonald 2011), as well as identified by our laboratory in several affected individuals. The variant is reported in ClinVar (Variation ID: 213216) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 11, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Nishida T et al. Brain arteriovenous malformations associated with hereditary hemorrhagic telangiectasia: gene-phenotype correlations. Am J Med Genet A. 2012 Nov;158A(11):2829-34. 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;79(4):335-344. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 06, 2023	PP3, PM2_supporting, PS4, PVS1_strong -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 08, 2023	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22991266, 21158752) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.1428+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 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; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, the impacted region is critical for protein function (Ambry internal data). This variant was reported in multiple individuals with features consistent with hereditary hemorrhagic telangiectasia (McDonald J, Clin. Genet. 2011;79(4):335-44; Nishida T et al. Am. J. Med. Genet. A. 2012 Nov;158A(11):2829-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is conserved in available vertebrate species. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

This sequence change affects a donor splice site in intron 11 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 hemorrhagic telangiectasia (PMID: 21158752, 22991266; Invitae). ClinVar contains an entry for this variant (Variation ID: 213216). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.89	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		4.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs863223542; hg19: chr9-130580994;