Variant 9-127843094-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The NM_001114753.3(ENG):c.219G>A(p.Thr73Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ENG
NM_001114753.3 splice_region, synonymous

Scores

Splicing: ADA: 0.9098

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7B:1

Conservation

PhyloP100: -0.364

Variant links:

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]

ENG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 9-127843094-C-T is Pathogenic according to our data. Variant chr9-127843094-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 407128.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_benign=1, Pathogenic=4, Likely_pathogenic=3}.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3 linkuse as main transcript	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	2/15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	2/15	1	NM_001114753.3	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	2/14	1		ENSP00000341917.3	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.-328G>A		splice_region_variant	2/15	2		ENSP00000479015.1	F5GX88
ENG	ENST00000480266.6 linkuse as main transcript	c.-328G>A		5_prime_UTR_variant	2/15	2		ENSP00000479015.1	F5GX88

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251270

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ENG: BP4, BP7 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2024	Published functional studies demonstrate that the c.219 G>A variant, which is part of the splice site consensus sequence in exon 2, leads to aberrant gene splicing and skipping of exon 2 (PMID: 17384219); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17384219, 34872578, 24196379) -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 05, 2017

- -

Telangiectasia, hereditary hemorrhagic, type 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Heidelberg University

Oct 27, 2023

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Nov 29, 2021

The ENG c.219G>A variant is at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant has been previously reported to disrupt splicing, resulting in a frameshift and loss-of-function, in an individual reported as having hereditary hemorrhagic telangiectasia (PMID: 17384219). -

ENG-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 26, 2023

Variant summary: ENG c.219G>A (p.Thr73Thr) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (examples: Gedge_2007). The variant allele was found at a frequency of 1.6e-05 in 251270 control chromosomes (gnomAD). c.219G>A has been reported in the literature in individuals affected with Hereditary Hemorrhagic Telangiectasia (examples: Gedge_2007 and Kitayama_2021). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 17384219, 34872578). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

The c.219G>A variant (also known as p.T73T) is located in coding exon 2 of the ENG gene. This variant results from a G to A substitution at nucleotide position 219. This nucleotide substitution does not change the threonine at codon 73. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in multiple individuals with hereditary hemorrhagic telangiectasia (HHT) (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; Komiyama M et al. J. Hum. Genet., 2014 Jan;59:37-41; Ambry internal data). In addition, mRNA studies showed exon 2 skipping (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary hemorrhagic telangiectasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 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 is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 407128). This variant has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 17384219, 24196379; Invitae). This variant is present in population databases (rs755348996, gnomAD 0.004%). This sequence change affects codon 73 of the ENG mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ENG protein. This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.91

dbscSNV1_RF

Pathogenic

0.87

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over