9-127825789-G-A

Position:

chr9-127825789-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001114753.3(ENG):c.595C>T(p.Arg199Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000884 in 1,594,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.04

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015449345).

BP6

Variant 9-127825789-G-A is Benign according to our data. Variant chr9-127825789-G-A is described in ClinVar as [Benign]. Clinvar id is 407127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-127825789-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ENG	NM_001114753.3 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	5/15	ENST00000373203.9	NP_001108225.1
ENG	NM_000118.4 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	5/14		NP_000109.1
ENG	NM_001278138.2 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	5/15		NP_001265067.1
ENG	NM_001406715.1 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	5/8		NP_001393644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	5/15	1	NM_001114753.3	ENSP00000362299	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.595C>T	p.Arg199Cys	missense_variant	5/14	1		ENSP00000341917	A2	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.49C>T	p.Arg17Cys	missense_variant	5/15	2		ENSP00000479015
ENG	ENST00000462196.1 linkuse as main transcript	n.495C>T		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000176

AC:

AN:

205002

Hom.:

AF XY:

0.000160

AC XY:

AN XY:

112436

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000324

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00154

Gnomad NFE exome

AF:

0.0000681

Gnomad OTH exome

AF:

0.000383

GnomAD4 exome

AF:

0.0000825

AC:

119

AN:

1442146

Hom.:

Cov.:

AF XY:

0.0000797

AC XY:

AN XY:

715620

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000237

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00122

Gnomad4 NFE exome

AF:

0.0000489

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.000145

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000761

AC:

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

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

Dec 09, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

T;T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.84

T;T;D

M_CAP

Benign

0.040

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;.;L

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-2.1

N;.;N

REVEL

Benign

0.071

Sift

Uncertain

0.018

D;.;D

Sift4G

Benign

0.073

T;D;T

Polyphen

1.0

D;.;.

Vest4

0.34

MutPred

0.47

Gain of catalytic residue at P198 (P = 0.0097);.;Gain of catalytic residue at P198 (P = 0.0097);

MVP

0.58

MPC

0.78

ClinPred

0.075

GERP RS

2.5

Varity_R

0.18

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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