rs1554812253

Variant names:

• chr9-127843093-C-T
• rs1554812253
• NM_001114753.3:c.219+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.219+1G>A variant causes a splice donor, intron 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 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:2
• Conservation: PhyloP100: 3.60

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 0.076884165 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.7, offset of 24, new splice context is: cggGTgggg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127843093-C-T is Pathogenic according to our data. Variant chr9-127843093-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 458343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.219+1G>A		splice_donor_variant, intron_variant	Intron 2 of 14	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.219+1G>A		splice_donor_variant, intron_variant	Intron 2 of 13		NP_000109.1
ENG	NM_001278138.2	c.-328+1G>A		splice_donor_variant, intron_variant	Intron 2 of 14		NP_001265067.1
ENG	NM_001406715.1	c.219+1G>A		splice_donor_variant, intron_variant	Intron 2 of 7		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.219+1G>A		splice_donor_variant, intron_variant	Intron 2 of 14	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.219+1G>A		splice_donor_variant, intron_variant	Intron 2 of 13	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-328+1G>A		splice_donor_variant, intron_variant	Intron 2 of 14	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1

Feb 22, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change affects a donor splice site in intron 2 of the ENG gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with ENG-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 458343). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). -

Cardiovascular phenotype Pathogenic:1

Apr 19, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.219+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the ENG gene. A disease-causing mutation, c.219+1G>T, has been described as the same nucleotide (Tørring PM et al. Clin. Genet., 2014 Aug;86:123-33). 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 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	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.83	D
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		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: rs1554812253; hg19: chr9-130605372;