chr7-100803532-C-T

Position:

chr7-100803532-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS2

The NM_004444.5(EPHB4):c.2893G>A(p.Val965Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000345 in 1,449,232 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

EPHB4
NM_004444.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.259

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030675739).

BP6

Variant 7-100803532-C-T is Benign according to our data. Variant chr7-100803532-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2539546.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB4	NM_004444.5 linkuse as main transcript	c.2893G>A	p.Val965Ile	missense_variant	17/17	ENST00000358173.8	NP_004435.3
EPHB4	XM_017011816.2 linkuse as main transcript	c.2947G>A	p.Val983Ile	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.2893G>A	p.Val965Ile	missense_variant	17/17	1	NM_004444.5	ENSP00000350896	P1	P54760-1
EPHB4	ENST00000360620.7 linkuse as main transcript	c.2737G>A	p.Val913Ile	missense_variant	16/16	1		ENSP00000353833
EPHB4	ENST00000487222.5 linkuse as main transcript	n.4094G>A		non_coding_transcript_exon_variant	16/16	1
EPHB4	ENST00000616502.4 linkuse as main transcript	c.*1358G>A		3_prime_UTR_variant	14/14	5		ENSP00000482702		P54760-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000871

AC:

AN:

229630

Hom.:

AF XY:

0.0000162

AC XY:

AN XY:

123622

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:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1449232

Hom.:

Cov.:

AF XY:

0.00000556

AC XY:

AN XY:

719170

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:

0.0000479

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

This alteration is classified as likely 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

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.060

.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.81

T;D

M_CAP

Benign

0.0050

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.77

.;N

MutationTaster

Benign

0.93

D;D

PrimateAI

Uncertain

0.48

PROVEAN

Benign

0.36

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0010

B;B

Vest4

0.061

MutPred

0.48

.;Gain of helix (P = 0.062);

MVP

0.13

MPC

0.39

ClinPred

0.13

GERP RS

3.8

Varity_R

0.054

gMVP

0.45

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