7-100818628-A-G

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.1314T>C(p.Ser438Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.6 in 1,610,268 control chromosomes in the GnomAD database, including 292,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24821 hom., cov: 32)

Exomes 𝑓: 0.60 ( 267416 hom. )

Consequence

EPHB4
NM_004444.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.14

Publications

30 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=-0.9).

BP6

Variant 7-100818628-A-G is Benign according to our data. Variant chr7-100818628-A-G is described in ClinVar as Benign. ClinVar VariationId is 811643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.651 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.1314T>C	p.Ser438Ser	synonymous_variant	Exon 7 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.1368T>C	p.Ser456Ser	synonymous_variant	Exon 7 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.1314T>C	p.Ser438Ser	synonymous_variant	Exon 7 of 17	1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes

AF:

0.566

AC:

85910

AN:

151828

Hom.:

24814

Cov.:

show subpopulations

Gnomad AFR

AF:

0.450

Gnomad AMI

AF:

0.634

Gnomad AMR

AF:

0.661

Gnomad ASJ

AF:

0.559

Gnomad EAS

AF:

0.632

Gnomad SAS

AF:

0.608

Gnomad FIN

AF:

0.569

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.603

Gnomad OTH

AF:

0.604

GnomAD2 exomes

AF:

0.611

AC:

150452

AN:

246310

AF XY:

0.612

show subpopulations

Gnomad AFR exome

AF:

0.445

Gnomad AMR exome

AF:

0.696

Gnomad ASJ exome

AF:

0.539

Gnomad EAS exome

AF:

0.647

Gnomad FIN exome

AF:

0.578

Gnomad NFE exome

AF:

0.608

Gnomad OTH exome

AF:

0.608

GnomAD4 exome

AF:

0.604

AC:

880797

AN:

1458322

Hom.:

267416

Cov.:

AF XY:

0.605

AC XY:

438860

AN XY:

725572

show subpopulations

African (AFR)

AF:

0.453

AC:

15155

AN:

33472

American (AMR)

AF:

0.693

AC:

30879

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

14187

AN:

26118

East Asian (EAS)

AF:

0.664

AC:

26334

AN:

39664

South Asian (SAS)

AF:

0.636

AC:

54834

AN:

86204

European-Finnish (FIN)

AF:

0.578

AC:

29274

AN:

50618

Middle Eastern (MID)

AF:

0.697

AC:

4021

AN:

5766

European-Non Finnish (NFE)

AF:

0.603

AC:

670271

AN:

1111558

Other (OTH)

AF:

0.594

AC:

35842

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

19900

39801

59701

79602

99502

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18186

36372

54558

72744

90930

<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:

0.566

AC:

85949

AN:

151946

Hom.:

24821

Cov.:

AF XY:

0.570

AC XY:

42321

AN XY:

74236

show subpopulations

African (AFR)

AF:

0.450

AC:

18674

AN:

41476

American (AMR)

AF:

0.661

AC:

10090

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.559

AC:

1939

AN:

3470

East Asian (EAS)

AF:

0.632

AC:

3252

AN:

5146

South Asian (SAS)

AF:

0.608

AC:

2927

AN:

4812

European-Finnish (FIN)

AF:

0.569

AC:

6002

AN:

10540

Middle Eastern (MID)

AF:

0.741

AC:

218

AN:

294

European-Non Finnish (NFE)

AF:

0.603

AC:

41002

AN:

67944

Other (OTH)

AF:

0.604

AC:

1268

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1915

3830

5745

7660

9575

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

738

1476

2214

2952

3690

<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:

0.594

Hom.:

80912

Bravo

AF:

0.568

Asia WGS

AF:

0.577

AC:

2008

AN:

3478

EpiCase

AF:

0.615

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Sep 21, 2018

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

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

-0.90

CADD

Benign

0.028

(source)

DANN

Benign

0.49

PhyloP100

-3.1

Mutation Taster

=99/1

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over