9-127854342-G-A

Position:

chr9-127854342-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001114753.3(ENG):c.14C>T(p.Thr5Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0226 in 1,593,366 control chromosomes in the GnomAD database, including 753 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 259 hom., cov: 32)

Exomes 𝑓: 0.020 ( 494 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.282

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018308163).

BP6

Variant 9-127854342-G-A is Benign according to our data. Variant chr9-127854342-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127854342-G-A is described in Lovd as [Benign]. Variant chr9-127854342-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 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.14C>T	p.Thr5Met	missense_variant	1/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4 linkuse as main transcript	c.14C>T	p.Thr5Met	missense_variant	1/14		NP_000109.1
ENG	NM_001406715.1 linkuse as main transcript	c.14C>T	p.Thr5Met	missense_variant	1/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.14C>T	p.Thr5Met	missense_variant	1/15	1	NM_001114753.3	ENSP00000362299	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.14C>T	p.Thr5Met	missense_variant	1/14	1		ENSP00000341917	A2	P17813-2

Frequencies

GnomAD3 genomes

AF:

0.0434

AC:

6610

AN:

152188

Hom.:

259

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0357

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00682

Gnomad FIN

AF:

0.00612

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0218

Gnomad OTH

AF:

0.0440

GnomAD3 exomes

AF:

0.0215

AC:

4471

AN:

207920

Hom.:

AF XY:

0.0192

AC XY:

2166

AN XY:

112672

show subpopulations

Gnomad AFR exome

AF:

0.108

Gnomad AMR exome

AF:

0.0191

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00721

Gnomad FIN exome

AF:

0.00499

Gnomad NFE exome

AF:

0.0214

Gnomad OTH exome

AF:

0.0220

GnomAD4 exome

AF:

0.0204

AC:

29394

AN:

1441060

Hom.:

494

Cov.:

AF XY:

0.0197

AC XY:

14060

AN XY:

715048

show subpopulations

Gnomad4 AFR exome

AF:

0.115

Gnomad4 AMR exome

AF:

0.0199

Gnomad4 ASJ exome

AF:

0.0222

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00699

Gnomad4 FIN exome

AF:

0.00559

Gnomad4 NFE exome

AF:

0.0198

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0435

AC:

6621

AN:

152306

Hom.:

259

Cov.:

AF XY:

0.0410

AC XY:

3057

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.104

Gnomad4 AMR

AF:

0.0356

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00724

Gnomad4 FIN

AF:

0.00612

Gnomad4 NFE

AF:

0.0218

Gnomad4 OTH

AF:

0.0436

Alfa

AF:

0.0269

Hom.:

103

Bravo

AF:

0.0489

TwinsUK

AF:

0.0232

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.101

AC:

445

ESP6500EA

AF:

0.0229

AC:

196

ExAC

AF:

0.0216

AC:

2596

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2014	Thr5Met in exon 1 of ENG: This variant is not expected to have clinical signific ance because it has been identified in 10% (445/4390) of African American chromo somes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs35400405). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2014	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	-	- -

Telangiectasia, hereditary hemorrhagic, type 1

Benign:3

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 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

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

Hereditary hemorrhagic telangiectasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 21, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.5

DANN

Benign

0.75

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0018

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.10

N;N

REVEL

Benign

0.0030

Sift

Benign

0.15

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0020

B;.

Vest4

0.019

MPC

0.22

ClinPred

0.00060

GERP RS

0.097

Varity_R

0.014

gMVP

0.48

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