7-100822277-A-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004444.5(EPHB4):c.802T>C(p.Cys268Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPHB4
NM_004444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 9.32

Publications

3 publications found

Variant links:

Genes affected

EPHB4 (HGNC:3395): (EPH receptor B4) Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. [provided by RefSeq, Jul 2008]

EPHB4 Gene-Disease associations (from GenCC):

capillary malformation-arteriovenous malformation 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
EPHB4-associated vascular malformation spectrum
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
lymphatic malformation 7
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
capillary malformation-arteriovenous malformation syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

EPHB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.982

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.802T>C	p.Cys268Arg	missense_variant	Exon 4 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.802T>C	p.Cys268Arg	missense_variant	Exon 4 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.802T>C	p.Cys268Arg	missense_variant	Exon 4 of 17	1	NM_004444.5	ENSP00000350896.3		P54760-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1408302

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696050

African (AFR)

AF:

0.00

AC:

AN:

31868

American (AMR)

AF:

0.00

AC:

AN:

38782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25338

East Asian (EAS)

AF:

0.00

AC:

AN:

36378

South Asian (SAS)

AF:

0.00

AC:

AN:

80454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083712

Other (OTH)

AF:

0.00

AC:

AN:

58242

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Capillary malformation-arteriovenous malformation 2

Pathogenic:1Uncertain:1

Mar 29, 2019

SIB Swiss Institute of Bioinformatics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as Uncertain significance for Capillary malformation-arteriovenous malformation 2. The following ACMG Tag(s) were applied: PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. -

Nov 27, 2018

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.75

T;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

3.5

.;H;H

PhyloP100

9.3

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-9.4

D;D;.

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.95

MutPred

0.84

Loss of ubiquitination at K267 (P = 0.0539);Loss of ubiquitination at K267 (P = 0.0539);Loss of ubiquitination at K267 (P = 0.0539);

MVP

0.92

MPC

1.8

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.97

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over