7-100803476-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004444.5(EPHB4):​c.2949G>A​(p.Pro983Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,575,378 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P983P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

EPHB4
NM_004444.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

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=-0.83).
BP6
Variant 7-100803476-C-T is Benign according to our data. Variant chr7-100803476-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1798004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.555 with no splicing effect.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000171 (26/152298) while in subpopulation EAS AF= 0.00444 (23/5178). AF 95% confidence interval is 0.00304. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EPHB4NM_004444.5 linkc.2949G>A p.Pro983Pro synonymous_variant Exon 17 of 17 ENST00000358173.8 NP_004435.3
EPHB4XM_017011816.2 linkc.3003G>A p.Pro1001Pro synonymous_variant Exon 17 of 17 XP_016867305.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EPHB4ENST00000358173.8 linkc.2949G>A p.Pro983Pro synonymous_variant Exon 17 of 17 1 NM_004444.5 ENSP00000350896.3 P54760-1
EPHB4ENST00000360620.7 linkc.2793G>A p.Pro931Pro synonymous_variant Exon 16 of 16 1 ENSP00000353833.3 Q96L35
EPHB4ENST00000487222.5 linkn.4150G>A non_coding_transcript_exon_variant Exon 16 of 16 1
EPHB4ENST00000616502 linkc.*1414G>A 3_prime_UTR_variant Exon 14 of 14 5 ENSP00000482702.1 P54760-3

Frequencies

GnomAD3 genomes
AF:
0.000177
AC:
27
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00462
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.000532
AC:
108
AN:
203110
Hom.:
0
AF XY:
0.000506
AC XY:
55
AN XY:
108778
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000356
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00671
Gnomad SAS exome
AF:
0.0000392
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000113
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000197
AC:
280
AN:
1423080
Hom.:
2
Cov.:
30
AF XY:
0.000195
AC XY:
137
AN XY:
702580
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000255
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00610
Gnomad4 SAS exome
AF:
0.0000123
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000376
Gnomad4 OTH exome
AF:
0.0000340
GnomAD4 genome
AF:
0.000171
AC:
26
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00444
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000946
Bravo
AF:
0.000234

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Sep 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1
May 20, 2019
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
BayesDel_noAF
Benign
-0.83
CADD
Benign
5.2
DANN
Benign
0.69
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; COSMIC: COSV62268821; COSMIC: COSV62268821; API