rs1060501408

Positions:

• chr9-127854482-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The NM_001114753.3(ENG):​c.-127C>T variant causes a 5 prime UTR 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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.70

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 Likely_pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id 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/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.-127C>T		5_prime_UTR_variant	1/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.-127C>T		5_prime_UTR_variant	1/14		NP_000109.1
ENG	NM_001406715.1	c.-127C>T		5_prime_UTR_variant	1/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.-127C>T		5_prime_UTR_variant	1/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.-127C>T		5_prime_UTR_variant	1/14	1		ENSP00000341917	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 877902 Hom.: 0 Cov.: 11 AF XY: 0.00 AC XY: 0 AN XY: 441396

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 26, 2023	PP1_strong, PM2_supporting, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2024	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, 32573726, 32300199, 35387445, 34872578) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 16, 2018	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. -

Hereditary hemorrhagic telangiectasia Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 21, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 25, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 08, 2024	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. -

Telangiectasia, hereditary hemorrhagic, type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2018

PM2+PP4+PP5 -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 15, 2022

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	23
DANN	Benign	0.96

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

Other links and lift over

dbSNP: rs1060501408; hg19: chr9-130616761;