rs1554813783

chr9-127854288-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):c.67+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. 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: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENG NM_001114753.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.31

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 20 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease,
• 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 9-127854288-C-T is Pathogenic according to our data. Variant chr9-127854288-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 449321.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127854288-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.67+1G>A		splice_donor_variant		ENST00000373203.9
ENG	NM_000118.4	c.67+1G>A		splice_donor_variant
ENG	NM_001406715.1	c.67+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.67+1G>A		splice_donor_variant		1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.67+1G>A		splice_donor_variant		1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1433484 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 710518

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2016	The c.67+1 G>A variant has been reported in multiple individuals who meet Curacao clinical criteria for a diagnosis of HHT and is recognized as a founder mutation in the Leeward Islands of the Netherlands Antilles; Bonaire and Curacao (Gallione et al., 2000; Letteboer et al., 2005). The c.67+1G>A variant destroys the canonical splice donor site in intron 1 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other splice site variants in the ENG gene, including several in the same splice donor site but a different nucleotide, have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, the c.67+1 G>A variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, c.67+1 G>A in the ENG gene is interpreted as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 22, 2019	PVS1, PS4, PM2 -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2000

- -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 15, 2023

This sequence change affects a donor splice site in intron 1 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: 10982033, 25970827). This variant is also known as IVS1+1 (g‚Üía). ClinVar contains an entry for this variant (Variation ID: 449321). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.67+1G>A intronic pathogenic mutation (also known as IVS1+1G>A) results from a G to A substitution one nucleotide after intron 1 of the ENG gene. This mutation was observed in 7 families with hereditary hemorrhagic telangiectasia (HHT) from the Dutch Antilles, and segregated with disease in all affected individuals (Gallione CJ et al. Hum. Genet., 2000 Jul;107:40-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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	-0.030
Cadd	Pathogenic	33
Dann	Uncertain	0.99
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.84	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		4.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -3
DS_DL_spliceai		0.96		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: rs1554813783; hg19: chr9-130616567;