NM_001114753.3:c.1311G>A

Variant names:

• chr9-127819622-C-T
• rs1554809448
• NM_001114753.3:c.1311G>A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001114753.3(ENG):​c.1311G>A​(p.Arg437Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG NM_001114753.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.94

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]

ENSG00000225032 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-127819622-C-T is Pathogenic according to our data. Variant chr9-127819622-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 854739.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127819622-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1311G>A	p.Arg437Arg	splice_region_variant, synonymous_variant	Exon 10 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1311G>A	p.Arg437Arg	splice_region_variant, synonymous_variant	Exon 10 of 14		NP_000109.1
ENG	NM_001278138.2	c.765G>A	p.Arg255Arg	splice_region_variant, synonymous_variant	Exon 10 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1568+911C>T		intron_variant	Intron 4 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1311G>A	p.Arg437Arg	splice_region_variant, synonymous_variant	Exon 10 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Dec 04, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ENG c.1311G>A; p.Arg437Arg variant is reported in the literature in five individuals affected with hereditary hemorrhagic telangiectasia (HHT) (Letteboer 2005). The five affected individuals with this variant were determined to share a common ancestor in the year 1745 (Letteboer 2005), suggesting the variant has segregated with disease over numerous meioses. The c.1311G>A variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is a synonymous variant in a moderately conserved nucleotide at the end of exon 10, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, although this has not yet been verified by RNA studies. Still, other variants at the same nucleotide (c.1311G>C, c.1311G>T) have been reported in individuals with HHT and are considered disease-causing (Gallione 1998, McDonald 2011), suggesting this position may be intolerant to sequence variation. Based on available information, the c.1311G>A variant is considered to be pathogenic. References: Gallione CJ et al. Mutation and expression analysis of the endoglin gene in hereditary hemorrhagic telangiectasia reveals null alleles. Hum Mutat. 1998;11(4):286-94. Letteboer TG et al. Hereditary hemorrhagic telangiectasia: ENG and ALK-1 mutations in Dutch patients. Hum Genet. 2005 Jan;116(1-2):8-16. 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. -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Aug 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 437 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 10, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 15517393). ClinVar contains an entry for this variant (Variation ID: 854739). 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. This variant disrupts the c.1311G nucleotide in the ENG gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 9554745, 21158752). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Apr 09, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1311G>A variant (also known as p.R437R), located in coding exon 10 of the ENG gene, results from a G to A substitution at nucleotide position 1311. This nucleotide substitution does not change the at codon 437. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. This mutation was detected in multiple individuals meeting clinical diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT) (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16). In addition, other alterations at this nucleotide position, c.1311G>C and c.1311G>T, have also been described in numerous unrelated individuals with HHT (Gallione CJ et al. Hum. Mutat., 1998;11:286-94; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.64		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: rs1554809448; hg19: chr9-130581901;