7-100803476-C-A

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

2

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]

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/exons MANE Protein UniProt
EPHB4NM_004444.5 linkuse as main transcriptc.2949G>T p.Pro983Pro synonymous_variant 17/17 ENST00000358173.8 NP_004435.3
EPHB4XM_017011816.2 linkuse as main transcriptc.3003G>T p.Pro1001Pro synonymous_variant 17/17 XP_016867305.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPHB4ENST00000358173.8 linkuse as main transcriptc.2949G>T p.Pro983Pro synonymous_variant 17/171 NM_004444.5 ENSP00000350896.3 P54760-1
EPHB4ENST00000360620.7 linkuse as main transcriptc.2793G>T p.Pro931Pro synonymous_variant 16/161 ENSP00000353833.3 Q96L35
EPHB4ENST00000487222.5 linkuse as main transcriptn.4150G>T non_coding_transcript_exon_variant 16/161
EPHB4ENST00000616502.4 linkuse as main transcriptc.*1414G>T 3_prime_UTR_variant 14/145 ENSP00000482702.1 P54760-3

Frequencies

GnomAD3 genomes
AF:
0.0231
AC:
3509
AN:
152170
Hom.:
115
Cov.:
32
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.:
40
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.:
30
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.:
32
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.:
17
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
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 18, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMay 06, 2021- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 16, 2023- -
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 23, 2020This 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.

Other links and lift over

dbSNP: rs112803997; hg19: chr7-100401098; API