chr7-100803477-G-A

Position:

chr7-100803477-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004444.5(EPHB4):c.2948C>T(p.Pro983Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,575,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P983P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

EPHB4
NM_004444.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14973018).

BS2

High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB4	NM_004444.5 linkuse as main transcript	c.2948C>T	p.Pro983Leu	missense_variant	17/17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 linkuse as main transcript	c.3002C>T	p.Pro1001Leu	missense_variant	17/17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8 linkuse as main transcript	c.2948C>T	p.Pro983Leu	missense_variant	17/17	1	NM_004444.5	ENSP00000350896	P1	P54760-1
EPHB4	ENST00000360620.7 linkuse as main transcript	c.2792C>T	p.Pro931Leu	missense_variant	16/16	1		ENSP00000353833
EPHB4	ENST00000487222.5 linkuse as main transcript	n.4149C>T		non_coding_transcript_exon_variant	16/16	1
EPHB4	ENST00000616502.4 linkuse as main transcript	c.*1413C>T		3_prime_UTR_variant	14/14	5		ENSP00000482702		P54760-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000147

AC:

AN:

204082

Hom.:

AF XY:

0.0000183

AC XY:

AN XY:

109280

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000224

Gnomad OTH exome

AF:

0.000192

GnomAD4 exome

AF:

0.0000176

AC:

AN:

1423284

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

702666

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000193

Gnomad4 OTH exome

AF:

0.0000340

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

EPHB4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 08, 2023

The EPHB4 c.2948C>T variant is predicted to result in the amino acid substitution p.Pro983Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0022% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-100401099-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The p.P983L variant (also known as c.2948C>T), located in coding exon 17 of the EPHB4 gene, results from a C to T substitution at nucleotide position 2948. The proline at codon 983 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.082

.;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.71

T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.15

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.4

.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.74

N;N

REVEL

Benign

0.090

Sift

Benign

0.084

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.58

P;P

Vest4

0.14

MutPred

0.18

.;Gain of catalytic residue at P983 (P = 0.0149);

MVP

0.49

MPC

1.3

ClinPred

0.64

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.071

gMVP

0.79

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over