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GeneBe

9-127854355-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_001114753.3(ENG):​c.1A>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ENG
NM_001114753.3 start_lost

Scores

5
6
5

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.63
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 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_001114753.3 (ENG) was described as [Pathogenic] in ClinVar as 458346
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-127854355-T-G is Pathogenic according to our data. Variant chr9-127854355-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 578951.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ENGNM_001114753.3 linkuse as main transcriptc.1A>C p.Met1? start_lost 1/15 ENST00000373203.9
ENGNM_000118.4 linkuse as main transcriptc.1A>C p.Met1? start_lost 1/14
ENGNM_001406715.1 linkuse as main transcriptc.1A>C p.Met1? start_lost 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ENGENST00000373203.9 linkuse as main transcriptc.1A>C p.Met1? start_lost 1/151 NM_001114753.3 P2P17813-1
ENGENST00000344849.4 linkuse as main transcriptc.1A>C p.Met1? start_lost 1/141 A2P17813-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Hereditary hemorrhagic telangiectasia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeMar 17, 2018Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500, 20656886, 22385575). This sequence change affects the initiator methionine of the ENG mRNA. The next in-frame methionine is located at codon 183. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with ENG-related disease. Other variants that affect the initiator methionine (c.1A>T, c.3G>T, c.1A>G, c.2T>C) have been reported in several individuals with hereditary hemorrhagic telangiectasia (PMID: 20414677, 15517393, 9554745). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.090
CADD
Benign
20
DANN
Benign
0.94
DEOGEN2
Benign
0.31
T;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.35
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Benign
-0.74
T
MutationTaster
Benign
1.0
D;D;D
PROVEAN
Benign
-1.2
N;N
REVEL
Uncertain
0.45
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
0.98
D;.
Vest4
0.95
MutPred
1.0
Loss of catalytic residue at M1 (P = 0.0979);Loss of catalytic residue at M1 (P = 0.0979);
MVP
0.92
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.92
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1060501418; hg19: chr9-130616634; API