rs148002300

Positions:

• chr9-127815951-G-A
• chr9-127815951-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1 BP5 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID:15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID:25312062, 22022569). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA211415/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (2 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign reviewed by expert panel B:16
• Conservation: PhyloP100: 2.10

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_benign. Variant got -6 ACMG points.

• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1844C>T	p.Ser615Leu	missense_variant	14/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1844C>T	p.Ser615Leu	missense_variant	14/14		NP_000109.1
ENG	NM_001278138.2	c.1298C>T	p.Ser433Leu	missense_variant	14/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1844C>T	p.Ser615Leu	missense_variant	14/15	1	NM_001114753.3	ENSP00000362299.4
ENG	ENST00000344849.4	c.1844C>T	p.Ser615Leu	missense_variant	14/14	1		ENSP00000341917.3
ENG	ENST00000480266.6	c.1298C>T	p.Ser433Leu	missense_variant	14/15	2		ENSP00000479015.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00238

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00154 AC: 345 AN: 224358 Hom.: 0 AF XY: 0.00153 AC XY: 186 AN XY: 121364

Gnomad AFR exome AF: 0.000649

Gnomad AMR exome AF: 0.000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000592

Gnomad SAS exome AF: 0.000828

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00254

Gnomad OTH exome AF: 0.00108

GnomAD4 exome AF: 0.00206 AC: 2985 AN: 1447230 Hom.: 2 Cov.: 31 AF XY: 0.00202 AC XY: 1452 AN XY: 718594

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.000472

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000281

Gnomad4 SAS exome AF: 0.000955

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.00245

Gnomad4 OTH exome AF: 0.00135

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00146 AC XY: 109 AN XY: 74492

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00133

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00129 AC: 156

ClinVar

Significance: Likely benign

Submissions summary: Benign:16

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:6

Benign, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	BS1 +BP2+BP6 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Benign, for Telangiectasia, hereditary hemorrhagic, type 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder (http://exac.broadinstitute.org/variant/9-130578230-G-A). BS2-Supporting => BS2 downgraded in strength to supporting. BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:15712270). -
Likely benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.1844C>T variant in ENG is a missense variant predicted to cause substitution of serine by leucine at amino acid 615 (p.Ser615Leu). The filtering allele frequency (the lower threshold of the 95% CI of 285/115780) of the c.1844C>T variant in ENG is 0.002284 for European (non-Finnish) chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.002) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 1 patient with an alternate molecular basis for disease (patient also carries a likely pathogenic/pathogenic ACVRL1 variant) (BP5; PMID: 15712270). The computational predictor REVEL gives a score of 0.188, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. However, cellular assays in NIH-3T3 cells showed that BMP9 binding and BMP9 response were all normal, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062, 22022569). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: BS1, BP5, BS3_Supporting (specification version 1.0.0; 1/4/2024). -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	ENG: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2020	This variant is associated with the following publications: (PMID: 15712270, 24055113, 25637381, 22022569, 25312062, 30487145) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.4% (108/26946) European chromosomes -

Haemorrhagic telangiectasia 1 Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary hemorrhagic telangiectasia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.35
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.022	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.;M
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-4.1	D;.;D
REVEL	Benign	0.19
Sift	Benign	0.065	T;.;T
Sift4G	Uncertain	0.053	T;D;T
Polyphen		0.11	B;.;.
Vest4		0.81
MVP		0.83
MPC		0.23
ClinPred		0.040	T
GERP RS		1.6
Varity_R		0.16
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs148002300; hg19: chr9-130578230;