rs1800956

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000373203.9(ENG):c.1096G>C(p.Asp366His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00399 in 1,613,884 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D366G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0047 ( 35 hom., cov: 30)

Exomes 𝑓: 0.0039 ( 198 hom. )

Consequence

ENG
ENST00000373203.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.23

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain in ENST00000373203.9

BP4

Computational evidence support a benign effect (MetaRNN=0.0020808578).

BP6

Variant 9-127824342-C-G is Benign according to our data. Variant chr9-127824342-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 163406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127824342-C-G is described in Lovd as [Benign]. Variant chr9-127824342-C-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ENG	NM_001114753.3 linkuse as main transcript	c.1096G>C	p.Asp366His	missense_variant	8/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4 linkuse as main transcript	c.1096G>C	p.Asp366His	missense_variant	8/14		NP_000109.1
ENG	NM_001278138.2 linkuse as main transcript	c.550G>C	p.Asp184His	missense_variant	8/15		NP_001265067.1
ENG	NM_001406715.1 linkuse as main transcript	c.1096G>C	p.Asp366His	missense_variant	8/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.1096G>C	p.Asp366His	missense_variant	8/15	1	NM_001114753.3	ENSP00000362299	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.1096G>C	p.Asp366His	missense_variant	8/14	1		ENSP00000341917	A2	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.550G>C	p.Asp184His	missense_variant	8/15	2		ENSP00000479015
ENG	ENST00000486329.1 linkuse as main transcript	n.64G>C		non_coding_transcript_exon_variant	1/3	2

Frequencies

GnomAD3 genomes

AF:

0.00472

AC:

717

AN:

151896

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00217

Gnomad ASJ

AF:

0.00260

Gnomad EAS

AF:

0.100

Gnomad SAS

AF:

0.00374

Gnomad FIN

AF:

0.000756

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00962

GnomAD3 exomes

AF:

0.00919

AC:

2311

AN:

251480

Hom.:

123

AF XY:

0.00839

AC XY:

1141

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00337

Gnomad EAS exome

AF:

0.108

Gnomad SAS exome

AF:

0.00258

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00391

AC:

5723

AN:

1461870

Hom.:

198

Cov.:

AF XY:

0.00379

AC XY:

2755

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00272

Gnomad4 EAS exome

AF:

0.0829

Gnomad4 SAS exome

AF:

0.00306

Gnomad4 FIN exome

AF:

0.000543

Gnomad4 NFE exome

AF:

0.00126

Gnomad4 OTH exome

AF:

0.00995

GnomAD4 genome

AF:

0.00470

AC:

715

AN:

152014

Hom.:

Cov.:

AF XY:

0.00502

AC XY:

373

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00216

Gnomad4 ASJ

AF:

0.00260

Gnomad4 EAS

AF:

0.100

Gnomad4 SAS

AF:

0.00354

Gnomad4 FIN

AF:

0.000756

Gnomad4 NFE

AF:

0.000927

Gnomad4 OTH

AF:

0.0105

Alfa

AF:

0.00423

Hom.:

Bravo

AF:

0.00529

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.00850

AC:

1032

Asia WGS

AF:

0.0500

AC:

172

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 04, 2014	Asp366His in exon 8 of ENG: This variant is not expected to have clinical signif icance because it has been identified in 10.5% (60/572) of Asian chromosomes by the 1000 Genomes Project (dbSNP rs1800956). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Telangiectasia, hereditary hemorrhagic, type 1

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Pulmonary arterial hypertension

Benign:1

Benign, no assertion criteria provided

clinical testing

John Welsh Cardiovascular Diagnostic Laboratory, Baylor College of Medicine

Sep 26, 2022

- -

ENG-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2022

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

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 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 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.78

D;D;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.54

T;T;T

MetaRNN

Benign

0.0021

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.1

M;.;M

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Benign

0.25

Sift

Uncertain

0.021

D;.;D

Sift4G

Uncertain

0.0060

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.30

MVP

0.83

MPC

0.87

ClinPred

0.023

GERP RS

3.6

Varity_R

0.23

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over