rs139334561

chr9-127854349-G-Achr9-127854349-G-Cchr9-127854349-G-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_001114753.3(ENG):c.7C>T(p.Arg3Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000526 in 1,590,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 0.778

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-127854348-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 975983.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.04701963).

BP6

Variant 9-127854349-G-A is Benign according to our data. Variant chr9-127854349-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 374952.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}. Variant chr9-127854349-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ENG	NM_001114753.3 linkuse as main transcript	c.7C>T	p.Arg3Cys	missense_variant	1/15	ENST00000373203.9
ENG	NM_000118.4 linkuse as main transcript	c.7C>T	p.Arg3Cys	missense_variant	1/14
ENG	NM_001406715.1 linkuse as main transcript	c.7C>T	p.Arg3Cys	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.7C>T	p.Arg3Cys	missense_variant	1/15	1	NM_001114753.3	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.7C>T	p.Arg3Cys	missense_variant	1/14	1		A2	P17813-2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000286

AC:

AN:

202648

Hom.:

AF XY:

0.000328

AC XY:

AN XY:

109604

show subpopulations

Gnomad AFR exome

AF:

0.000163

Gnomad AMR exome

AF:

0.0000661

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000114

Gnomad NFE exome

AF:

0.000600

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000558

AC:

803

AN:

1437944

Hom.:

Cov.:

AF XY:

0.000558

AC XY:

398

AN XY:

713314

show subpopulations

Gnomad4 AFR exome

AF:

0.000182

Gnomad4 AMR exome

AF:

0.0000969

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000606

Gnomad4 FIN exome

AF:

0.000117

Gnomad4 NFE exome

AF:

0.000695

Gnomad4 OTH exome

AF:

0.000286

GnomAD4 genome

AF:

0.000217

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000630

Hom.:

Bravo

AF:

0.000264

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000350

AC:

ExAC

AF:

0.000225

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2018	BS1 +BP2 -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Apr 04, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2020	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15312062, 25312062) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 08, 2019

- -

ENG-related condition

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 11, 2022

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). -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 11, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.51

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.61

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.059

Sift

Benign

0.064

T;T

Sift4G

Uncertain

0.0050

D;D

Polyphen

0.029

B;.

Vest4

0.13

MVP

0.49

MPC

0.95

ClinPred

0.11

GERP RS

3.0

Varity_R

0.090

gMVP

0.81

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