9-127829682-C-T

Position:

• chr9-127829682-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001114753.3(ENG):​c.360+5G>A variant causes a splice donor 5th base, 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 benign 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: 31)
• Consequence: ENG NM_001114753.3 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 14 ACMG points.

• 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 9-127829682-C-T is Pathogenic according to our data. Variant chr9-127829682-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 810952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127829682-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.360+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000373203.9
ENG	NM_000118.4	c.360+5G>A		splice_donor_5th_base_variant, intron_variant
ENG	NM_001278138.2	c.-187+5G>A		splice_donor_5th_base_variant, intron_variant
ENG	NM_001406715.1	c.360+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.360+5G>A		splice_donor_5th_base_variant, intron_variant		1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.360+5G>A		splice_donor_5th_base_variant, intron_variant		1		A2
ENG	ENST00000480266.6	c.-187+5G>A		splice_donor_5th_base_variant, intron_variant		2
ENG	ENST00000462196.1	n.118+5G>A		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 06, 2019	The ENG c.360+5G>A variant is reported in the literature in an individual with a clinical diagnosis of HHT (Letteboer 2005). In addition, other changes affecting this +5 position (c.360+4_7delAGTG, c.360+5G>C, c.360+5G>T), are also reported in individuals suspected to have HHT (Gedge 2007, Lux 2013). The c.360+5G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a well conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by abolishing the nearby canonical donor splice site. Based on available information, the c.360+5G>A variant is considered to be likely pathogenic. REFERENCES Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Lux A et al. HHT diagnosis by Mid-infrared spectroscopy and artificial neural network analysis. Orphanet J Rare Dis. 2013 Jun 27;8:94. -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PM2+PP3+PP4 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 02, 2022

PP3, PM1, PM2, PS4_moderate -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 03, 2023

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has been observed in individual(s) with hereditary hemorrhagic telangiectasia (PMID: 15517393, 32573726; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 3 of the ENG gene. It does not directly change the encoded amino acid sequence of the ENG protein. It affects a nucleotide within the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 810952). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 15, 2016

The c.360+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 3 in the ENG gene. This variant has been reported in an individual with a clinical diagnosis of hereditary hemorrhagic telangiectasia (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). In our clinical cohort, this variant was detected in an individual with epistaxis, telangiectasias, pulmonary ateriovenous malformations, and a family history of hereditary hemorrhagic telangiectasia. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501417; hg19: chr9-130591961;