Genetic Variant EPHB4:n.980A>C (chr7-100824547-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000487222.5(EPHB4):n.980A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.618 in 443,646 control chromosomes in the GnomAD database, including 85,489 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.60 ( 27403 hom., cov: 33)

Exomes 𝑓: 0.63 ( 58086 hom. )

Consequence

EPHB4
ENST00000487222.5 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.84

Publications

9 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.99).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.53-274A>C		intron_variant	Intron 1 of 16	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.53-274A>C		intron_variant	Intron 1 of 16		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.53-274A>C		intron_variant	Intron 1 of 16	1	NM_004444.5	ENSP00000350896.3		P54760-1

Frequencies

GnomAD3 genomes

AF:

0.598

AC:

90831

AN:

151908

Hom.:

27394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.526

Gnomad AMI

AF:

0.633

Gnomad AMR

AF:

0.681

Gnomad ASJ

AF:

0.604

Gnomad EAS

AF:

0.630

Gnomad SAS

AF:

0.628

Gnomad FIN

AF:

0.611

Gnomad MID

AF:

0.803

Gnomad NFE

AF:

0.613

Gnomad OTH

AF:

0.633

GnomAD4 exome

AF:

0.629

AC:

183364

AN:

291620

Hom.:

58086

Cov.:

AF XY:

0.631

AC XY:

96541

AN XY:

152960

show subpopulations

African (AFR)

AF:

0.532

AC:

4695

AN:

8818

American (AMR)

AF:

0.689

AC:

8648

AN:

12558

Ashkenazi Jewish (ASJ)

AF:

0.601

AC:

5315

AN:

8848

East Asian (EAS)

AF:

0.674

AC:

13915

AN:

20636

South Asian (SAS)

AF:

0.662

AC:

19278

AN:

29108

European-Finnish (FIN)

AF:

0.618

AC:

11460

AN:

18558

Middle Eastern (MID)

AF:

0.721

AC:

893

AN:

1238

European-Non Finnish (NFE)

AF:

0.621

AC:

108562

AN:

174810

Other (OTH)

AF:

0.622

AC:

10598

AN:

17046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

3235

6471

9706

12942

16177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.598

AC:

90873

AN:

152026

Hom.:

27403

Cov.:

AF XY:

0.603

AC XY:

44792

AN XY:

74320

show subpopulations

African (AFR)

AF:

0.526

AC:

21813

AN:

41458

American (AMR)

AF:

0.681

AC:

10406

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.604

AC:

2097

AN:

3470

East Asian (EAS)

AF:

0.629

AC:

3245

AN:

5156

South Asian (SAS)

AF:

0.628

AC:

3026

AN:

4820

European-Finnish (FIN)

AF:

0.611

AC:

6467

AN:

10588

Middle Eastern (MID)

AF:

0.788

AC:

230

AN:

292

European-Non Finnish (NFE)

AF:

0.613

AC:

41677

AN:

67936

Other (OTH)

AF:

0.633

AC:

1336

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1916

3832

5748

7664

9580

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.599

Hom.:

4176

Bravo

AF:

0.600

Asia WGS

AF:

0.585

AC:

2039

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.31

(source)

DANN

Benign

0.50

PhyloP100

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

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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7-100824547-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over