9-127825704-T-C

Position:

chr9-127825704-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_001114753.3(ENG):c.680A>G(p.His227Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,582,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H227H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

ENG
NM_001114753.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.81

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 9 uncertain in NM_001114753.3

BP4

Computational evidence support a benign effect (MetaRNN=0.052363783).

BP6

Variant 9-127825704-T-C is Benign according to our data. Variant chr9-127825704-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572674.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ENG	NM_001114753.3 linkuse as main transcript	c.680A>G	p.His227Arg	missense_variant	5/15	ENST00000373203.9
ENG	NM_000118.4 linkuse as main transcript	c.680A>G	p.His227Arg	missense_variant	5/14
ENG	NM_001278138.2 linkuse as main transcript	c.134A>G	p.His45Arg	missense_variant	5/15
ENG	NM_001406715.1 linkuse as main transcript	c.680A>G	p.His227Arg	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENG	ENST00000373203.9 linkuse as main transcript	c.680A>G	p.His227Arg	missense_variant	5/15	1	NM_001114753.3	P2	P17813-1
ENG	ENST00000344849.4 linkuse as main transcript	c.680A>G	p.His227Arg	missense_variant	5/14	1		A2	P17813-2
ENG	ENST00000480266.6 linkuse as main transcript	c.134A>G	p.His45Arg	missense_variant	5/15	2

Frequencies

GnomAD3 genomes

AF:

0.0000133

AC:

AN:

150528

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000577

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:

0.0000193

AC:

AN:

207034

Hom.:

AF XY:

0.00000873

AC XY:

AN XY:

114552

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000471

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:

0.0000112

AC:

AN:

1432050

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

709930

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000358

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000364

Gnomad4 OTH exome

AF:

0.0000508

GnomAD4 genome

AF:

0.0000133

AC:

AN:

150528

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73408

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000577

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:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000253

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Telangiectasia, hereditary hemorrhagic, type 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 08, 2021

- -

Hereditary hemorrhagic telangiectasia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.6

DANN

Benign

0.52

DEOGEN2

Benign

0.41

T;T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.51

T;T;T

M_CAP

Benign

0.0049

MetaRNN

Benign

0.052

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;N

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.95

N;.;N

REVEL

Benign

0.016

Sift

Benign

0.55

T;.;T

Sift4G

Benign

0.80

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.061

MVP

0.20

MPC

0.26

ClinPred

0.019

GERP RS

1.5

Varity_R

0.071

gMVP

0.33

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