9-127854364-C-T

Position:

• chr9-127854364-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP5 PS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.-9G>A variant is located in the 5' UTR of ENG. Because the variant is located in the 5' UTR, is it not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007942 (76/95698 alleles) in the European (non-Finnish) population. This variant has been observed in patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ACVRL1 variant) (BP5; Internal lab contributors). Expression studies showed this variant causes a small reduction (~18.4%) of endoglin compared to wild type (PS3_Supporting, PMID:22192717). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS3_Supporting, BP5 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5253269/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00082 (1 hom.)
• Consequence: ENG NM_001114753.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:7 B:3
• Conservation: PhyloP100: 0.0650

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.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.-9G>A		5_prime_UTR_premature_start_codon_gain_variant	1/15	ENST00000373203.9	NP_001108225.1
ENG	NM_001114753.3	c.-9G>A		5_prime_UTR_variant	1/15	ENST00000373203.9	NP_001108225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.-9G>A		5_prime_UTR_premature_start_codon_gain_variant	1/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.-9G>A		5_prime_UTR_premature_start_codon_gain_variant	1/14	1		ENSP00000341917.3
ENG	ENST00000373203.9	c.-9G>A		5_prime_UTR_variant	1/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.-9G>A		5_prime_UTR_variant	1/14	1		ENSP00000341917.3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000517 AC: 99 AN: 191406 Hom.: 0 AF XY: 0.000524 AC XY: 54 AN XY: 103090

Gnomad AFR exome AF: 0.000263

Gnomad AMR exome AF: 0.000172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000634

Gnomad FIN exome AF: 0.000294

Gnomad NFE exome AF: 0.000847

Gnomad OTH exome AF: 0.000398

GnomAD4 exome AF: 0.000815 AC: 1167 AN: 1431220 Hom.: 1 Cov.: 31 AF XY: 0.000822 AC XY: 583 AN XY: 709318

Gnomad4 AFR exome AF: 0.000153

Gnomad4 AMR exome AF: 0.000174

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000722

Gnomad4 FIN exome AF: 0.000196

Gnomad4 NFE exome AF: 0.000965

Gnomad4 OTH exome AF: 0.000439

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74338

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000620

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000758 Hom.: 0

Bravo AF: 0.000408

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:7 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Jan 14, 2022	This substitution variant occurs in the 5'UTR of the ENG gene and it introduces a premature start codon 9bp prior to the existing start codon, maintaining the reading frame but elongating the protein by three additional amino acid residues. This variant has been observed in gnomAD with a total MAF of 0.0549% across multiple subpopulations, but occurring with the highest MAF of 0.0921% in the European population; these frequencies are inconsistent with the disease frequency. This position is not conserved. This variant has been identified in the literature in both families and individuals with hereditary hemorrhagic telangiectasia, both in the heterozygous state and homozygous state (HHT) (PMID: 21158752, 22192717); segregation of the variant within affected families has been inconsistent or incompletely assessed (PMID: 22192717). A single in vitro protein expression study suggested that this variant may be hypomorphic after it demonstrated that this variant causes decreased expression of the protein, to only ~80% of the wild-type, and it was suggested that this may be a mild variant when heterozygous and cause a more classic HHT presentation when homozygous, where expression dropped to ~60% of the wild-type (PMID: 22192717). In the literature, this variant has also been called benign or a polymorphism due to its frequency in a population of individuals with suspected or possible HHT (PMID: 17384219). Considering this variant occurs relatively frequently, despite having been observed in some individuals and families who are affected, the impact of this variant and segregation with disease require further investigations to elucidate pathogenicity; thus this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 20, 2022	BS1, PP1, PM4, PS3_supporting, PS4_moderate -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1 Uncertain:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 03, 2021	The ENG c.-9G>A variant (rs368423516 ) has been described in the literature in families with hereditary hemorrhagic telangiectasia or pulmonary arterial hypertension and has been reported as a hypomorphic allele causing reduced functionality (Best 2017, Kim 2011, McDonald 2011, McDonald 2020). Additionally, this variant has been shown to cause reduced translation (Damjanovich 2011). The variant is listed in the ClinVar database (Variation ID: 414302) and in the general population with an allele frequency of 0.05% (108/222760 alleles) in the Genome Aggregation Database. The nucleotide at the -9 position is moderately conserved across mammals and creates a novel methionine translational start, leading to the inclusion of additional amino acids. Due to its description in the literature as a hypomorphic allele with reduced translation, we consider the c.-9G>A variant to be pathogenic with mild clinical outcomes. References: Best DH et al. EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension. Chest. 2017 Apr;151(4):821-828 Damjanovich K et al. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011 Dec 22;6:85. Kim MJ et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011 Oct 3;12:130. McDonald J et al. Curacao diagnostic criteria for hereditary hemorrhagic telangiectasia is highly predictive of a pathogenic variant in ENG or ACVRL1 (HHT1 and HHT2). Genet Med. 2020 Jul;22(7):1201-1205. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44. -
Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.-9G>A variant is located in the 5' UTR of ENG. Because the variant is located in the 5' UTR, is it not expected to alter the amino acid sequence. The highest population minor allele frequency in gnomAD v2.1.1 is 0.0007942 (76/95698 alleles) in the European (non-Finnish) population. This variant has been observed in patients with an alternate molecular basis for disease (patients also carry a likely pathogenic/pathogenic ACVRL1 variant) (BP5; Internal lab contributors). Expression studies showed this variant causes a small reduction (approximately 18.4%) of endoglin compared to wild type (PS3_Supporting, PMID: 22192717). Due to conflicting evidence, this variant is classified as a variant of uncertain significance for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS3_Supporting, BP5 (specification version 1.0.0; 1/4/2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 23, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary hemorrhagic telangiectasia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 07, 2023	This sequence change in ENG is located in the 5' untranslated region. It introduces an alternative initiation codon three residues upstream from the existing initiation codon. In vitro protein expression analyses showed the variant decreases protein expression by around 20% (PMID: 22192717). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.08% (76/95,698 alleles) in the European (non-Finnish) population. This variant has been described as a hypomorphic allele and reported in at least three probands (one homozygous) with epistaxis and telangiectasia suggestive of hereditary haemorrhagic telangiectasia but without visceral arteriovenous malformations (PMID: 22192717). It has also been reported in a proband with idiopathic primary arterial hypertension (PMID: 27884767). The variant has been reported to segregate with epistaxis and telangiectasia in multiple individuals from two families (PMID: 22192717). The variant has conflicting pathogenicity interpretations in ClinVar (ID: 414302). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 07, 2022	This variant occurs in a non-coding region of the ENG gene. It does not change the encoded amino acid sequence of the ENG protein. This variant is present in population databases (rs368423516, gnomAD 0.09%). This variant has been observed in individual(s) with clinical features of hereditary hemhorrhagic telangiectasia (PMID: 21158752, 22192717, 32300199; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 414302). Studies have shown that this variant alters ENG gene expression (PMID: 22192717). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 14, 2023

Variant summary: ENG c.-9G>A is located in the untranslated mRNA region upstream of the initiation codon, predicted to introduce a premature start codon. The variant allele was found at a frequency of 0.00052 in 191406 control chromosomes. The observed variant frequency is approximately 12.41 fold of the estimated maximal expected allele frequency for a pathogenic variant in ENG causing Hereditary Hemorrhagic Telangiectasia phenotype (4.2e-05), these frequencies are inconsistent with disease frequencies. c.-9G>A has been reported in the literature in heterozygous and homozygous individuals affected with symptoms of Hereditary Hemorrhagic Telangiectasia (Damjanovich_2011, Gedge_2007, McDonald_2011). Segregation was observed in some families. Functional studies of this variant showed that expression of the mutant protein was reduced approximately 20% compared to the wild type protein (Damjanovich_2011). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=3), Likely Pathogenic (n=1) and Pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2022

The c.-9G>A alteration is located in the 5' untranslated region (5'UTR) of the ENG gene. This alteration consists of a G to A substitution 9 nucleotides upstream from the first translated codon. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

ENG-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs368423516; hg19: chr9-130616643;