rs764262721

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: The NM_001114753.3: c.1711C>T variant in ENG is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 571 (p.Arg571Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004233 (15/35434 alleles) in the Admixed American population. The computational predictor REVEL gives a score of 0.31, 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 a variant of uncertain significance 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: None (specification version 1.0.0; 1/4/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA5252673/MONDO:0008535/136

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4B:1

Conservation

PhyloP100: 4.33

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:

ENSG00000225032 (HGNC:):

ENSG00000225032 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 linkuse as main transcript	c.1165C>T	p.Arg389Cys	missense_variant	13/15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
LOC102723566	NR_136302.1 linkuse as main transcript	n.1114G>A		non_coding_transcript_exon_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/15	1	NM_001114753.3	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.1711C>T	p.Arg571Cys	missense_variant	13/14	1		ENSP00000341917.3	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.1165C>T	p.Arg389Cys	missense_variant	13/15	2		ENSP00000479015.1	F5GX88
ENSG00000225032	ENST00000439298.5 linkuse as main transcript	n.1114G>A		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251344

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000294

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:2

Uncertain significance, reviewed by expert panel	curation	ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	Mar 15, 2024	The NM_001114753.3: c.1711C>T variant in ENG is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 571 (p.Arg571Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0004233 (15/35434 alleles) in the Admixed American population. The computational predictor REVEL gives a score of 0.31, 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 a variant of uncertain significance 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: None (specification version 1.0.0; 1/4/2024). -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 24, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2016

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: Variant reported in 1 proband with juvenile polyposis -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 17, 2015

- -

Hereditary hemorrhagic telangiectasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.67

D;T;.

Eigen

Benign

0.0034

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.48

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Benign

0.038

MetaRNN

Pathogenic

0.93

D;D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Benign

0.24

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.81

MutPred

0.83

Gain of sheet (P = 0.0827);.;Gain of sheet (P = 0.0827);

MVP

0.85

MPC

0.82

ClinPred

0.37

GERP RS

3.6

Varity_R

0.21

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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