rs1060501408

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_001114753.3(ENG):c.-127C>T variant causes a 5 prime UTR premature start codon gain 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. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ENG
NM_001114753.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.70

Publications

11 publications found

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]

ENG Gene-Disease associations (from GenCC):

telangiectasia, hereditary hemorrhagic, type 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen
hereditary hemorrhagic telangiectasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
juvenile polyposis syndrome
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-127854482-G-A is Pathogenic according to our data. Variant chr9-127854482-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 407113.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3 link	c.-127C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_001114753.3 link	c.-127C>T		5_prime_UTR_variant	Exon 1 of 15	ENST00000373203.9	NP_001108225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 link	c.-127C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000373203.9 link	c.-127C>T		5_prime_UTR_variant	Exon 1 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

877902

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

441396

African (AFR)

AF:

0.00

AC:

AN:

19704

American (AMR)

AF:

0.00

AC:

AN:

24756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17404

East Asian (EAS)

AF:

0.00

AC:

AN:

31948

South Asian (SAS)

AF:

0.00

AC:

AN:

58082

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3074

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

647632

Other (OTH)

AF:

0.00

AC:

AN:

39820

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Feb 18, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

No data available from control populations to assess the frequency of this variant; Published functional studies demonstrate that this variant leads to decreased levels of protein expression and creates a new translation start site that leads to nonsense-mediated mRNA decay (PMID: 21967607, 22192717); This variant is associated with the following publications: (PMID: 22192717, 28989145, 21967607, 36651276, 32573726, 32300199, 35387445, 34872578) -

Mar 16, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ENG c.-127C>T variant (rs1060501408) has been reported to segregate with disease in families affected with hereditary hemorrhagic telangiectasia (HHT) (Damjanovich 2011, Kim 2011). This variant is reported as pathogenic in ClinVar (Variation ID: 407113) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. In vitro functional analyses of this variant demonstrate generation of an aberrant translational start codon and decreased endoglin expression (Damjanovich 2011, Kim 2011). Based on the above information, this variant is considered pathogenic. References: Damjanovich K et al. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011 Dec 22;6:85. Kim M et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011 Oct 3;12:130. -

Jul 13, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 26, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PM2_supporting, PS3, PS4_moderate -

Telangiectasia, hereditary hemorrhagic, type 1

Pathogenic:3

Apr 25, 2024

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2018

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PM2+PP4+PP5 -

Sep 24, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: 5' UTR variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 21967607). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 21967607). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000407113 /PMID: 21967607). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Hereditary hemorrhagic telangiectasia

Pathogenic:3

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant occurs in a non-coding region of the ENG gene. It does not change the encoded amino acid sequence of the ENG protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hereditary hemorrhagic telangiectasia (PMID: 21967607, 22192717, 28989145). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 407113). Studies have shown that this variant alters ENG gene expression (PMID: 21967607, 22192717). For these reasons, this variant has been classified as Pathogenic. -

Mar 08, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-127C>T variant in ENG has been reported in at least 5 unrelated individuals with hereditary hemorrhagic telangiectasia (HHT) and segregated with disease in 10 affected individuals from 3 families (Kim 2011 PMID: 21967607, Damjanovich 2011 PMID: 22192717). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 407113). In vitro functional studies support an impact on gene expression (Kim 2011 PMID: 21967607, Damjanovich 2011 PMID: 22192717). Heterozygous loss of ENG function is an established disease mechanism in individuals with HHT. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HHT. ACMG/AMP Criteria applied: PP1_strong, PS4, PS3_moderate, PM2_supporting. -

Nov 25, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Pathogenic:1

Jun 15, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.-127C>T pathogenic mutation is located in the 5' untranslated region (5’ UTR) of the ENG gene. This variant results from a C to T substitution 127 nucleotides upstream from the first translated codon. This mutation was first reported in four unrelated individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT); in two families, the mutation segregated with disease (Damjanovich K et al. Orphanet J Rare Dis, 2011 Dec;6:85). In another study, this mutation segregated with disease in five members of a Korean family with HHT (Kim MJ et al. BMC Med. Genet., 2011 Oct;12:130). In addition, this mutation resulted in a 78% reduction in protein level when expressed in COS7 cells due to decreased efficiency in protein transcriptional and translational mechanisms (Damjanovich K et al. Orphanet J Rare Dis, 2011 Dec;6:85). 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

-0.33

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

2.7

PromoterAI

-0.13

Neutral

(source)

Mutation Taster

=62/238

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over