rs2230585

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004444.5(EPHB4):c.1890C>T(p.Cys630Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.367 in 1,613,700 control chromosomes in the GnomAD database, including 112,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8562 hom., cov: 33)

Exomes 𝑓: 0.37 ( 103551 hom. )

Consequence

EPHB4
NM_004444.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.27

Publications

26 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 7-100812975-G-A is Benign according to our data. Variant chr7-100812975-G-A is described in ClinVar as [Benign]. Clinvar id is 811000.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.27 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.385 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.1890C>T	p.Cys630Cys	synonymous_variant	Exon 12 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.1944C>T	p.Cys648Cys	synonymous_variant	Exon 12 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.1890C>T	p.Cys630Cys	synonymous_variant	Exon 12 of 17	1	NM_004444.5	ENSP00000350896.3		P54760-1

Frequencies

GnomAD3 genomes

AF:

0.323

AC:

49027

AN:

151996

Hom.:

8558

Cov.:

show subpopulations

Gnomad AFR

AF:

0.197

Gnomad AMI

AF:

0.367

Gnomad AMR

AF:

0.287

Gnomad ASJ

AF:

0.428

Gnomad EAS

AF:

0.322

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.427

Gnomad MID

AF:

0.190

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.314

GnomAD2 exomes

AF:

0.341

AC:

85538

AN:

250944

AF XY:

0.343

show subpopulations

Gnomad AFR exome

AF:

0.195

Gnomad AMR exome

AF:

0.274

Gnomad ASJ exome

AF:

0.440

Gnomad EAS exome

AF:

0.314

Gnomad FIN exome

AF:

0.423

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.359

GnomAD4 exome

AF:

0.372

AC:

543540

AN:

1461584

Hom.:

103551

Cov.:

AF XY:

0.370

AC XY:

268864

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.190

AC:

6376

AN:

33480

American (AMR)

AF:

0.275

AC:

12300

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

11482

AN:

26130

East Asian (EAS)

AF:

0.294

AC:

11653

AN:

39696

South Asian (SAS)

AF:

0.258

AC:

22226

AN:

86250

European-Finnish (FIN)

AF:

0.421

AC:

22449

AN:

53260

Middle Eastern (MID)

AF:

0.275

AC:

1585

AN:

5768

European-Non Finnish (NFE)

AF:

0.390

AC:

433485

AN:

1111890

Other (OTH)

AF:

0.364

AC:

21984

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

23823

47646

71469

95292

119115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13430

26860

40290

53720

67150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.322

AC:

49043

AN:

152116

Hom.:

8562

Cov.:

AF XY:

0.320

AC XY:

23824

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.197

AC:

8174

AN:

41526

American (AMR)

AF:

0.287

AC:

4388

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.428

AC:

1483

AN:

3468

East Asian (EAS)

AF:

0.322

AC:

1664

AN:

5160

South Asian (SAS)

AF:

0.271

AC:

1305

AN:

4824

European-Finnish (FIN)

AF:

0.427

AC:

4524

AN:

10588

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.389

AC:

26454

AN:

67962

Other (OTH)

AF:

0.311

AC:

658

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

1585

3169

4754

6338

7923

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

486

972

1458

1944

2430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.363

Hom.:

16097

Bravo

AF:

0.309

Asia WGS

AF:

0.283

AC:

985

AN:

3478

EpiCase

AF:

0.378

EpiControl

AF:

0.383

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Lymphatic malformation 7

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 04, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Capillary malformation-arteriovenous malformation 2

Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

9.2

(source)

DANN

Benign

0.58

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over