9-127826640-CG-CGGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001114753.3(ENG):​c.391_392dupCC​(p.Gly132ArgfsTer32) 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: 32)

Consequence

ENG
NM_001114753.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.0560
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 9-127826640-C-CGG is Pathogenic according to our data. Variant chr9-127826640-C-CGG is described in ClinVar as [Pathogenic]. Clinvar id is 1736116.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ENGNM_001114753.3 linkc.391_392dupCC p.Gly132ArgfsTer32 frameshift_variant Exon 4 of 15 ENST00000373203.9 NP_001108225.1 P17813-1Q96CG0A0A024R878
ENGNM_000118.4 linkc.391_392dupCC p.Gly132ArgfsTer32 frameshift_variant Exon 4 of 14 NP_000109.1 P17813-2Q5T9B9
ENGNM_001406715.1 linkc.391_392dupCC p.Gly132ArgfsTer32 frameshift_variant Exon 4 of 8 NP_001393644.1
ENGNM_001278138.2 linkc.-156_-155dupCC 5_prime_UTR_variant Exon 4 of 15 NP_001265067.1 P17813Q96CG0F5GX88B7Z6Y5

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENGENST00000373203.9 linkc.391_392dupCC p.Gly132ArgfsTer32 frameshift_variant Exon 4 of 15 1 NM_001114753.3 ENSP00000362299.4 P17813-1
ENGENST00000344849.4 linkc.391_392dupCC p.Gly132ArgfsTer32 frameshift_variant Exon 4 of 14 1 ENSP00000341917.3 P17813-2
ENGENST00000480266.6 linkc.-156_-155dupCC 5_prime_UTR_variant Exon 4 of 15 2 ENSP00000479015.1 F5GX88
ENGENST00000462196.1 linkn.291_292dupCC non_coding_transcript_exon_variant Exon 3 of 4 3 ENSP00000519251.1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Pathogenic:1
Mar 23, 2015
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.391_392dupCC pathogenic mutation, located in coding exon 4 of the ENG gene, results from a duplication of CC at nucleotide positions 391 and 392, causing a translational frameshift with a predicted alternate stop codon. 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-130588919; API