9-127818173-C-T

Variant names:

• chr9-127818173-C-T
• rs142896669
• NM_001114753.3:c.1633G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP5 BS1_Supporting BP2

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID:18498373) which is classified as likely pathogenic (PMID:18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. 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_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252712/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (2 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:2 B:7
• Conservation: PhyloP100: 4.33

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]

ENSG00000225032 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENG	NM_001114753.3	c.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 14		NP_000109.1
ENG	NM_001278138.2	c.1087G>A	p.Gly363Ser	missense_variant	Exon 12 of 15		NP_001265067.1
LOC102723566	NR_136302.1	n.1378-138C>T		intron_variant	Intron 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.1633G>A	p.Gly545Ser	missense_variant	Exon 12 of 15	1	NM_001114753.3	ENSP00000362299.4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000521 AC: 131 AN: 251296 Hom.: 0 AF XY: 0.000456 AC XY: 62 AN XY: 135870

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1461876 Hom.: 2 Cov.: 31 AF XY: 0.000660 AC XY: 480 AN XY: 727242

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00159

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000771

Gnomad4 OTH exome AF: 0.000364

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000507 Hom.: 0

Bravo AF: 0.000491

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000519 AC: 63

EpiCase AF: 0.000654

EpiControl AF: 0.000771

ClinVar

Significance: Likely benign

Submissions summary: Pathogenic:1 Uncertain:2 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 0.12% (rs142896669, 54/35,428 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.4.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Sep 11, 2024

ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_001114753.3: c.1633G>A variant in ENG is a missense variant predicted to cause substitution of glycine by serine at amino acid 545 (p.Gly545Ser). The filtering allele frequency (the lower threshold of the 95% CI of 54/35,428 alleles) of the c.1633G>A variant in ENG is 0.1% for Admixed American chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.08%) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). This variant has been observed in trans with the variant c.391_392del, p.(Pro131Glyfs*17) (PMID: 18498373) which is classified as likely pathogenic (PMID: 18498373) in an individual with hereditary hemorrhagic telangiectasia. The phase of the variants was confirmed by family testing (BP2). This variant has been observed in at least two patients with an alternate molecular basis for disease (likely pathogenic/pathogenic variants identified in ACVRL1) (BP5; internal lab contributors). The computational predictor REVEL gives a score of 0.399, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. 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_Supporting, BP2, BP5 (specifications version 1.1.0; 09/11/2024). -

Pulmonary hypertension, primary, 1 Pathogenic:1

-

Rare Disease Genomics Group, St George's University of London

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: 2 probands, no segs in HGMD; ExAC: 0.2% (25/11560) Latino chromosomes -

Pulmonary arterial hypertension associated with congenital heart disease Uncertain:1

Jun 27, 2018

Wendy Chung Laboratory, Columbia University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: case-control

- -

ENG-related disorder Benign:1

Aug 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Oct 01, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype Benign:1

Jan 03, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.5	L;.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.057	T;.;D
Sift4G	Benign	0.095	T;T;D
Polyphen		1.0	D;.;.
Vest4		0.48
MVP		0.88
MPC		0.76
ClinPred		0.068	T
GERP RS		5.2
Varity_R		0.29
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142896669; hg19: chr9-130580452; COSMIC: COSV61226765; COSMIC: COSV61226765;