rs1064793734

Positions:

• chr9-127824313-CTCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001114753.3(ENG):​c.1121_1124del​(p.Lys374SerfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ENG NM_001114753.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 3.36

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-127824313-CTCTT-C is Pathogenic according to our data. Variant chr9-127824313-CTCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 419225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENG	NM_001114753.3	c.1121_1124del	p.Lys374SerfsTer6	frameshift_variant	8/15	ENST00000373203.9
ENG	NM_000118.4	c.1121_1124del	p.Lys374SerfsTer6	frameshift_variant	8/14
ENG	NM_001278138.2	c.575_578del	p.Lys192SerfsTer6	frameshift_variant	8/15
ENG	NM_001406715.1	c.1121_1124del	p.Lys374SerfsTer5	frameshift_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9	c.1121_1124del	p.Lys374SerfsTer6	frameshift_variant	8/15	1	NM_001114753.3	P2
ENG	ENST00000344849.4	c.1121_1124del	p.Lys374SerfsTer6	frameshift_variant	8/14	1		A2
ENG	ENST00000480266.6	c.575_578del	p.Lys192SerfsTer6	frameshift_variant	8/15	2
ENG	ENST00000486329.1	n.89_92del		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes Cov.: 30

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 12, 2015

The c.1121_1124delAAGA deletion in the ENG gene has been reported previously (reported asc.1120_1123 delAAAG due to alternate nomenclature) in one Japanese family with HHT (Dakeishi M etal., 2002). Furthermore, the c.1121_1124delAAGA variant was not observed in approximately 6,500individuals of European and African American ancestry in the NHLBI Exome Sequencing Project,indicating it is not a common benign variant in these populations. This deletion is expected to result in either anabnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNAdecay. Other frameshift variants in the ENG gene have been reported in HGMD in association withHHT (Stenson P et al., 2014). In summary, c.1121_1124delAAGA in the ENG gene is interpreted as a pathogenic variant. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2016

The c.1121_1124delAAGA pathogenic mutation, located in coding exon 8 of the ENG gene, results from a deletion of 4 nucleotides between nucleotide positions 1121 and 1124, causing a translational frameshift with a predicted alternate stop codon p.(K374Sfs*6). This mutation was described in an individual meeting clinical diagnostic criteria for HHT (Dakeishi M, Hum. Mutat. 2002 Feb; 19(2):140-8). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Hereditary hemorrhagic telangiectasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

This variant is also known as c.1120_1123delAAAG. This sequence change creates a premature translational stop signal (p.Lys374Serfs*6) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 11793473, 20501893; Invitae). ClinVar contains an entry for this variant (Variation ID: 419225). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1064793734; hg19: chr9-130586592;