rs1060501417

chr9-127829682-C-Gchr9-127829682-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>C 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:3
• 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-G is Pathogenic according to our data. Variant chr9-127829682-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 407129.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.360+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000373203.9
ENG	NM_000118.4	c.360+5G>C		splice_donor_5th_base_variant, intron_variant
ENG	NM_001278138.2	c.-187+5G>C		splice_donor_5th_base_variant, intron_variant
ENG	NM_001406715.1	c.360+5G>C		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>C		splice_donor_5th_base_variant, intron_variant		1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.360+5G>C		splice_donor_5th_base_variant, intron_variant		1		A2
ENG	ENST00000480266.6	c.-187+5G>C		splice_donor_5th_base_variant, intron_variant		2
ENG	ENST00000462196.1	n.118+5G>C		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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2017

A c.360+5 G>C variant that is likely pathogenic was identified in the ENG gene. The c.360+5 G>C variant has been previously reported in one individual with a confirmed clinical diagnosis of HHT (Gedge et al., 2007); although, further clinical details and segregation studies were not reported. The c.360+5 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In silico splice prediction programs predict this variant destroys the natural splice donor site in intron 3 which 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 have been reported in HGMD in association with HHT (Stenson et al., 2014). Furthermore, this substitution occurs at a nucleotide that is conserved in mammals. Finally, a likely pathogenic variant at the same nucleotide position (c.360+5 G>A) has also been reported in association with HHT (Letteboer et al., 2005), supporting the functional significance of this nucleotide. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 05, 2022

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. This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 17384219; Invitae). ClinVar contains an entry for this variant (Variation ID: 407129). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2021

The c.360+5G>C intronic pathogenic mutation results from a G to C substitution 5 nucleotides after coding exon 3 in the ENG gene. This variant has been reported in a patient clinically affected with hereditary hemorrhagic telangiectasia (HHT) (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). In addition, other variants affecting the same nucletotide position (G>A and G>T) have been detected in patients with HHT (Letteboer TG et al. Hum Genet, 2005 Jan;116:8-16; Lux A et al. Orphanet J Rare Dis, 2013 Jun;8:94). In addition, this mutation has been shown to segregate with disease (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. 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_noAF	Benign	-0.38
Cadd	Uncertain	25
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		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;