9-127843094-C-T

Variant names:

• chr9-127843094-C-T
• rs755348996
• NM_001114753.3:c.219G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

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:7 B:1
• Conservation: PhyloP100: -0.364

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 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, Likely_pathogenic=3, Pathogenic=4}.
• 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 rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	Exon 2 of 15	ENST00000373203.9	NP_001108225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	Exon 2 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.219G>A	p.Thr73Thr	splice_region_variant, synonymous_variant	Exon 2 of 14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.-328G>A		splice_region_variant	Exon 2 of 15	2		ENSP00000479015.1
ENG	ENST00000480266.6	c.-328G>A		5_prime_UTR_variant	Exon 2 of 15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251270 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135828

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: 12 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

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.: 31

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ENG: BP4, BP7 -

Sep 19, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Oct 27, 2023

Institute of Human Genetics, Heidelberg University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases Pathogenic:1

Nov 29, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 26, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant is present in population databases (rs755348996, gnomAD 0.004%). This variant has been observed in individuals with clinical features of hereditary hemorrhagic telangiectasia (PMID: 17384219, 24196379; Invitae). 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). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Jan 18, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
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

Other links and lift over

dbSNP: rs755348996; hg19: chr9-130605373;