rs1057515420

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.980C>T(p.Pro327Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,393,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P327P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPHB4
NM_004444.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.53

Publications

1 publications found

Variant links:

COSMIC-nc: COSV62270982

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, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.980C>T	p.Pro327Leu	missense_variant	Exon 6 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.980C>T	p.Pro327Leu	missense_variant	Exon 6 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 link	c.980C>T	p.Pro327Leu	missense_variant	Exon 6 of 17	1	NM_004444.5	ENSP00000350896.3		P54760-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1393024

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

685910

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31496

American (AMR)

AF:

0.00

AC:

AN:

35632

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25100

East Asian (EAS)

AF:

0.00

AC:

AN:

35582

South Asian (SAS)

AF:

0.00

AC:

AN:

79270

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47864

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5220

European-Non Finnish (NFE)

AF:

0.00000186

AC:

AN:

1075194

Other (OTH)

AF:

0.00

AC:

AN:

57666

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tetralogy of Fallot

Pathogenic:1

Jan 01, 2015

Andelfinger Lab, Centre de Recherche, CHU Sainte Justine

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not provided

Uncertain:1

Aug 07, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in at least one individual from a family with history of severe pulmonary stenosis, tetralogy of Fallot, and ventricular septal defects; however, additional details were not provided (Preuss et al., 2016); This variant is associated with the following publications: (PMID: 27760138) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

.;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.73

MutationAssessor

Pathogenic

3.4

.;M

PhyloP100

9.5

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-8.0

D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.88

MutPred

0.80

Loss of glycosylation at P327 (P = 0.0313);Loss of glycosylation at P327 (P = 0.0313);

MVP

0.82

MPC

1.4

ClinPred

1.0

GERP RS

5.5

Varity_R

0.75

gMVP

0.84

Mutation Taster

=33/67

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over