9-127826641-G-A

Position:

• chr9-127826641-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, 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 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: BA1 (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA202695/MONDO:0008535/136

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (49 hom.)
• Consequence: ENG NM_001114753.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:10
• Conservation: PhyloP100: -0.0560

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 Benign. Variant got -8 ACMG points.

• BA1: 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.392C>T	p.Pro131Leu	missense_variant	4/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4	c.392C>T	p.Pro131Leu	missense_variant	4/14		NP_000109.1
ENG	NM_001406715.1	c.392C>T	p.Pro131Leu	missense_variant	4/8		NP_001393644.1
ENG	NM_001278138.2	c.-155C>T		5_prime_UTR_variant	4/15		NP_001265067.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9	c.392C>T	p.Pro131Leu	missense_variant	4/15	1	NM_001114753.3	ENSP00000362299	P2
ENG	ENST00000344849.4	c.392C>T	p.Pro131Leu	missense_variant	4/14	1		ENSP00000341917	A2
ENG	ENST00000480266.6	c.-155C>T		5_prime_UTR_variant	4/15	2		ENSP00000479015
ENG	ENST00000462196.1	n.292C>T		non_coding_transcript_exon_variant	3/4	3

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 294 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.0127

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0280

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00112

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00461 AC: 1158 AN: 251006 Hom.: 10 AF XY: 0.00590 AC XY: 800 AN XY: 135674

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.0128

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0249

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00162

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00274 AC: 4012 AN: 1461634 Hom.: 49 Cov.: 32 AF XY: 0.00345 AC XY: 2510 AN XY: 727110

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0129

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0253

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.00100

Gnomad4 OTH exome AF: 0.00412

GnomAD4 genome AF: 0.00193 AC: 293 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74412

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.0127

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00133

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00511 AC: 621

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00231

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.392C>T variant in ENG is a missense variant predicted to cause substitution of proline by leucine at amino acid 131 (p.Pro131Leu). The filtering allele frequency (the lower threshold of the 95% CI of 762/30612) of the c.392C>T variant in ENG is 0.02343 for South Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.01) for BA1, and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.315, 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 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: BA1 (specification version 1.0.0; 1/4/2024). -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 01, 2023	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2018	This variant is associated with the following publications: (PMID: 32560555, 28655553, 27535533, 27146957, 12673790, 15879500, 25637381, 23399955, 21158752, 24055113) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	ENG: BP4, BS1, BS2 -

Haemorrhagic telangiectasia 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

Low GERP score may suggest that this variant may belong in a lower pathogenicity class -

Galloway-Mowat syndrome 1 Benign:1

Benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The heterozygous p.Pro131Leu variant in ENG has been identified in multiple individuals with haemorrhagic telangiectasia and individuals without haemorrhagic telangiectasia (PMID: 15879500, 21158752), and has been identified in >2% of South Asian chromosomes and 7 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal dominant haemorrhagic telangiectasia. -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 04, 2015

This alteration is classified as 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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.8
DANN	Benign	0.60
DEOGEN2	Uncertain	0.48	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.67	T;T
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Uncertain	0.32
Sift	Benign	0.12	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.066	B;.
Vest4		0.11
MVP		0.96
MPC		0.22
ClinPred		0.020	T
GERP RS		-1.9
Varity_R		0.22
gMVP		0.16

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: rs139398993; hg19: chr9-130588920;