7-100813656-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004444.5(EPHB4):c.1752A>G(p.Gly584Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.602 in 1,613,392 control chromosomes in the GnomAD database, including 293,754 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 25521 hom., cov: 31)

Exomes 𝑓: 0.60 ( 268233 hom. )

Consequence

EPHB4
NM_004444.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0220

Publications

31 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 7-100813656-T-C is Benign according to our data. Variant chr7-100813656-T-C is described in ClinVar as Benign. ClinVar VariationId is 811646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.022 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.1752A>G	p.Gly584Gly	synonymous_variant	Exon 10 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.1806A>G	p.Gly602Gly	synonymous_variant	Exon 10 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.1752A>G	p.Gly584Gly	synonymous_variant	Exon 10 of 17	1	NM_004444.5	ENSP00000350896.3		P54760-1

Frequencies

GnomAD3 genomes

AF:

0.576

AC:

87384

AN:

151738

Hom.:

25515

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.666

Gnomad ASJ

AF:

0.560

Gnomad EAS

AF:

0.626

Gnomad SAS

AF:

0.608

Gnomad FIN

AF:

0.571

Gnomad MID

AF:

0.769

Gnomad NFE

AF:

0.604

Gnomad OTH

AF:

0.613

GnomAD2 exomes

AF:

0.614

AC:

154237

AN:

251370

AF XY:

0.614

show subpopulations

Gnomad AFR exome

AF:

0.480

Gnomad AMR exome

AF:

0.700

Gnomad ASJ exome

AF:

0.540

Gnomad EAS exome

AF:

0.646

Gnomad FIN exome

AF:

0.577

Gnomad NFE exome

AF:

0.609

Gnomad OTH exome

AF:

0.610

GnomAD4 exome

AF:

0.604

AC:

883387

AN:

1461538

Hom.:

268233

Cov.:

AF XY:

0.605

AC XY:

440033

AN XY:

727110

show subpopulations

African (AFR)

AF:

0.488

AC:

16338

AN:

33476

American (AMR)

AF:

0.695

AC:

31087

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14200

AN:

26132

East Asian (EAS)

AF:

0.642

AC:

25465

AN:

39694

South Asian (SAS)

AF:

0.636

AC:

54846

AN:

86250

European-Finnish (FIN)

AF:

0.578

AC:

30795

AN:

53316

Middle Eastern (MID)

AF:

0.700

AC:

4035

AN:

5768

European-Non Finnish (NFE)

AF:

0.603

AC:

670597

AN:

1111800

Other (OTH)

AF:

0.597

AC:

36024

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

19584

39168

58753

78337

97921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18194

36388

54582

72776

90970

<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:

0.576

AC:

87420

AN:

151854

Hom.:

25521

Cov.:

AF XY:

0.580

AC XY:

43016

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.484

AC:

20047

AN:

41404

American (AMR)

AF:

0.666

AC:

10147

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.560

AC:

1939

AN:

3464

East Asian (EAS)

AF:

0.626

AC:

3225

AN:

5154

South Asian (SAS)

AF:

0.608

AC:

2928

AN:

4816

European-Finnish (FIN)

AF:

0.571

AC:

6020

AN:

10542

Middle Eastern (MID)

AF:

0.752

AC:

221

AN:

294

European-Non Finnish (NFE)

AF:

0.604

AC:

41023

AN:

67928

Other (OTH)

AF:

0.613

AC:

1293

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1897

3794

5692

7589

9486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

746

1492

2238

2984

3730

<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:

0.595

Hom.:

40995

Bravo

AF:

0.579

Asia WGS

AF:

0.576

AC:

2005

AN:

3478

EpiCase

AF:

0.616

EpiControl

AF:

0.610

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 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 12, 2019

GeneDx

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

- -

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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.8

(source)

DANN

Benign

0.57

PhyloP100

0.022

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over