9-127824304-C-T

Position:

• chr9-127824304-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.1134G>A​(p.Ala378Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A378A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENG NM_001114753.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.96

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127824304-C-T is Pathogenic according to our data. Variant chr9-127824304-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127824304-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1134G>A	p.Ala378Ala	splice_region_variant, synonymous_variant	8/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1134G>A	p.Ala378Ala	splice_region_variant, synonymous_variant	8/14		NP_000109.1
ENG	NM_001278138.2	c.588G>A	p.Ala196Ala	splice_region_variant, synonymous_variant	8/15		NP_001265067.1
ENG	NM_001406715.1	c.1134G>A	p.Ala378Ala	synonymous_variant	8/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1134G>A	p.Ala378Ala	splice_region_variant, synonymous_variant	8/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1134G>A	p.Ala378Ala	splice_region_variant, synonymous_variant	8/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.588G>A	p.Ala196Ala	splice_region_variant, synonymous_variant	8/15	2		ENSP00000479015.1
ENG	ENST00000486329.1	n.102G>A		splice_region_variant, non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 30

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2024	PP1_moderate, PP3, PP4, PP5, PM2, PS4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; This variant is associated with the following publications: (PMID: 24196379, 17786384, 20414677, 32303606, 16752392, 32503579, 32300199, 32573726, 15517393, 34872578) -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jun 04, 2020	- -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 01, 2019	The ENG c.1134G>A; p.Ala378Ala variant (rs1329127701) is reported in the literature in multiple individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Bossler 2006, Komiyama 2014, Letteboer 2005, Olivieri 2007, Richards-Yutz 2010). In addition, this variant has been identified in numerous affected individuals by testing performed at ARUP Laboratories. This variant is present on a single chromosomes (1/31364 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This is a synonymous variant in a moderately conserved nucleotide which is the last nucleotide in ENG exon 8, and computational analyses (Alamut v.2.11) predict that this variant impacts splicing by weakening the nearby canonical donor splice site. Based on available information, this variant is considered to be pathogenic. References: Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Komiyama M et al. Hereditary hemorrhagic telangiectasia in Japanese patients. J Hum Genet. 2014 Jan;59(1):37-41. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. Olivieri C et al. Analysis of ENG and ACVRL1 genes in 137 HHT Italian families identifies 76 different mutations (24 novel). Comparison with other European studies. J Hum Genet. 2007;52(10):820-9. Richards-Yutz J et al. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010 Jul;128(1):61-77. -
Likely pathogenic, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	PM2++PP3+ PP4+PP5 -

ENG-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2023

The ENG c.1134G>A variant is not predicted to result in an amino acid change (p.=). This variant is located at the last nucleotide position of exon 8 and is predicted to interfere with splicing at the consensus site based on splicing prediction programs. This variant has also been reported in several patients affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer et al. 2005. PubMed ID: 15517393, Bossler et al. 2006. PubMed ID: 16752392; Olivieri et al. 2007. PubMed ID: 17786384, Komiyama et al. 2014. PubMed ID: 24196379). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-130586583-C-T). Based on this evidence, we interpret this variant as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2024

The c.1134G>A variant (also known as p.A378A) is located in coding exon 8 of the ENG gene. This variant results from a G to A substitution at nucleotide position 1134. This nucleotide substitution does not change the alanine at codon 378. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This variant has been detected in multiple individuals with clinical diagnoses of hereditary hemorrhagic telangiectasia, including at least one demonstrating low level mosaicism (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; Olivieri C et al. J. Hum. Genet., 2007 Sep;52:820-9; Richards-Yutz J et al. Hum. Genet., 2010 Jul;128:61-77; Clarke JM et al. J. Med. Genet., 2020;57(12):859-862). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2023

This sequence change affects codon 378 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 8, which is part of the consensus splice site for this exon. This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (HHT) (PMID: 15517393, 17786384, 20414677, 24196379). This variant is also known as IVS8 ds G-A -1 and as A374A. ClinVar contains an entry for this variant (Variation ID: 458328). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Uncertain	24
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.71		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: 24
DS_DL_spliceai		0.71		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1329127701; hg19: chr9-130586583;