NM_004444.5:c.2949G>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004444.5(EPHB4):c.2949G>T(p.Pro983Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00526 in 1,575,352 control chromosomes in the GnomAD database, including 253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 117 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 136 hom. )

Consequence

EPHB4
NM_004444.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.555

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 7-100803476-C-A is Benign according to our data. Variant chr7-100803476-C-A is described in ClinVar as [Benign]. Clinvar id is 811022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100803476-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.555 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHB4	NM_004444.5 link	c.2949G>T	p.Pro983Pro	synonymous_variant	Exon 17 of 17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 link	c.3003G>T	p.Pro1001Pro	synonymous_variant	Exon 17 of 17		XP_016867305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EPHB4	ENST00000358173.8 link	c.2949G>T	p.Pro983Pro	synonymous_variant	Exon 17 of 17	1	NM_004444.5	ENSP00000350896.3	P54760-1
EPHB4	ENST00000360620.7 link	c.2793G>T	p.Pro931Pro	synonymous_variant	Exon 16 of 16	1		ENSP00000353833.3	Q96L35
EPHB4	ENST00000487222.5 link	n.4150G>T		non_coding_transcript_exon_variant	Exon 16 of 16	1
EPHB4	ENST00000616502 link	c.*1414G>T		3_prime_UTR_variant	Exon 14 of 14	5		ENSP00000482702.1	P54760-3

Frequencies

GnomAD3 genomes

AF:

0.0231

AC:

3509

AN:

152170

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0777

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00983

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00869

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000691

Gnomad OTH

AF:

0.0182

GnomAD3 exomes

AF:

0.00741

AC:

1506

AN:

203110

Hom.:

AF XY:

0.00656

AC XY:

714

AN XY:

108778

show subpopulations

Gnomad AFR exome

AF:

0.0780

Gnomad AMR exome

AF:

0.00438

Gnomad ASJ exome

AF:

0.00246

Gnomad EAS exome

AF:

0.0000639

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.00500

GnomAD4 exome

AF:

0.00335

AC:

4762

AN:

1423064

Hom.:

136

Cov.:

AF XY:

0.00335

AC XY:

2356

AN XY:

702568

show subpopulations

Gnomad4 AFR exome

AF:

0.0829

Gnomad4 AMR exome

AF:

0.00523

Gnomad4 ASJ exome

AF:

0.00309

Gnomad4 EAS exome

AF:

0.0000260

Gnomad4 SAS exome

AF:

0.0106

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000362

Gnomad4 OTH exome

AF:

0.00695

GnomAD4 genome

AF:

0.0231

AC:

3524

AN:

152288

Hom.:

117

Cov.:

AF XY:

0.0231

AC XY:

1717

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0778

Gnomad4 AMR

AF:

0.00975

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00911

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000691

Gnomad4 OTH

AF:

0.0175

Alfa

AF:

0.00747

Hom.:

Bravo

AF:

0.0263

ClinVar

Significance: Benign

Submissions summary: Benign:5

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

- -

Nov 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 23, 2020

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

-0.75

CADD

Benign

2.6

DANN

Benign

0.65

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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