rs763087751

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP4_ModerateBP6_ModerateBS2

The NM_001114753.3(ENG):c.627G>C(p.Leu209Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,600,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.584

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 Likely_benign. Variant got -6 ACMG points.

PM1

In a region_of_interest OR1, C-terminal part (size 130) in uniprot entity EGLN_HUMAN there are 10 pathogenic changes around while only 4 benign (71%) in NM_001114753.3

BP4

Computational evidence support a benign effect (MetaRNN=0.18421951).

BP6

Variant 9-127825757-C-G is Benign according to our data. Variant chr9-127825757-C-G is described in ClinVar as [Benign]. Clinvar id is 854175.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-127825757-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENG	NM_001114753.3 linkuse as main transcript	c.627G>C	p.Leu209Phe	missense_variant	5/15	ENST00000373203.9	NP_001108225.1	P17813-1Q96CG0A0A024R878
ENG	NM_000118.4 linkuse as main transcript	c.627G>C	p.Leu209Phe	missense_variant	5/14		NP_000109.1	P17813-2Q5T9B9
ENG	NM_001278138.2 linkuse as main transcript	c.81G>C	p.Leu27Phe	missense_variant	5/15		NP_001265067.1	P17813Q96CG0F5GX88B7Z6Y5
ENG	NM_001406715.1 linkuse as main transcript	c.627G>C	p.Leu209Phe	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.627G>C	p.Leu209Phe	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299.4	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.627G>C	p.Leu209Phe	missense_variant	5/14	1		ENSP00000341917.3	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.81G>C	p.Leu27Phe	missense_variant	5/15	2		ENSP00000479015.1	F5GX88
ENG	ENST00000462196.1 linkuse as main transcript	n.*32G>C		downstream_gene_variant		3		ENSP00000519251.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000921

AC:

AN:

217116

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

119128

show subpopulations

Gnomad AFR exome

AF:

0.000158

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000622

AC:

AN:

1448040

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719230

show subpopulations

Gnomad4 AFR exome

AF:

0.000270

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0000963

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.00000838

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary hemorrhagic telangiectasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.47

T;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.67

T;T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

N;.;N

REVEL

Benign

0.052

Sift

Benign

0.23

T;.;T

Sift4G

Benign

0.30

T;T;T

Polyphen

0.29

B;.;.

Vest4

0.29

MutPred

0.72

Gain of methylation at R205 (P = 0.1374);.;Gain of methylation at R205 (P = 0.1374);

MVP

0.50

MPC

0.30

ClinPred

0.034

GERP RS

2.5

Varity_R

0.27

gMVP

0.37

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