9-127819622-C-G

Position:

• chr9-127819622-C-G

Variant summary

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

The ENST00000373203.9(ENG):​c.1311G>C​(p.Arg437=) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R437R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ENG ENST00000373203.9 splice_region, synonymous
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely 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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127819622-C-G is Pathogenic according to our data. Variant chr9-127819622-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1311G>C	p.Arg437=	splice_region_variant, synonymous_variant	10/15	ENST00000373203.9	NP_001108225.1
LOC102723566	NR_136302.1	n.1568+911C>G		intron_variant, non_coding_transcript_variant
ENG	NM_000118.4	c.1311G>C	p.Arg437=	splice_region_variant, synonymous_variant	10/14		NP_000109.1
ENG	NM_001278138.2	c.765G>C	p.Arg255=	splice_region_variant, synonymous_variant	10/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1311G>C	p.Arg437=	splice_region_variant, synonymous_variant	10/15	1	NM_001114753.3	ENSP00000362299	P2
	ENST00000439298.5	n.1568+911C>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

May 04, 2022

PP1_strong, PM2_supporting, PVS1_moderate -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

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 individual(s) with hemorrhagic telangiectasia (PMID: 9554745). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458335). 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: 15517393). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2015

The c.1311G>C pathogenic mutation (also known as p.R437R), located in coding exon 10 of the ENG gene, results from a G to C substitution at nucleotide position 1311. This nucleotide substitution does not change the amino acid 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 showed complete segregation in a large kindred of 25 affected individuals with hereditary hemorrhagic telangiectasia (HHT) and was not observed in 115 normal control individuals (Gallione CJ et al. Hum. Mutat., 1998;11:286-94). In addition, other alterations at this nucleotide position, c.1311G>A and c.1311G>T, have also been described in numerous unrelated individuals with HHT and have been predicted to disrupt splicing (Letteboer TG et al. Hum. Genet., 2005 Jan;116:8-16; McDonald J et al. Clin. Genet., 2011 Apr;79:335-44). Using two different splice site prediction tools, the c.1311G>C alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however, direct evidence is unavailable. Based on the available evidence, c.1311G>C is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.74		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.74		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;