chr4-65365187-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001281766.3(EPHA5):​c.2003T>C​(p.Val668Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

EPHA5
NM_001281766.3 missense

Scores

13
5
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
Variant links:
Genes affected
EPHA5 (HGNC:3389): (EPH receptor A5) This gene belongs to the ephrin receptor subfamily of the protein-tyrosine kinase family. EPH and EPH-related receptors have been implicated in mediating developmental events, particularly in the nervous system. Receptors in the EPH subfamily typically have a single kinase domain and an extracellular region containing a Cys-rich domain and 2 fibronectin type III repeats. The ephrin 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. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EPHA5NM_001281766.3 linkuse as main transcriptc.2003T>C p.Val668Ala missense_variant 11/17 ENST00000613740.5 NP_001268695.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPHA5ENST00000613740.5 linkuse as main transcriptc.2003T>C p.Val668Ala missense_variant 11/171 NM_001281766.3 ENSP00000478537 A2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000566
Hom.:
0
Bravo
AF:
0.0000189

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 30, 2024The c.2066T>C (p.V689A) alteration is located in exon 12 (coding exon 12) of the EPHA5 gene. This alteration results from a T to C substitution at nucleotide position 2066, causing the valine (V) at amino acid position 689 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.71
D;D;.;D;.;D
Eigen
Pathogenic
0.92
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D
M_CAP
Pathogenic
0.34
D
MetaRNN
Pathogenic
0.97
D;D;D;D;D;D
MetaSVM
Uncertain
0.78
D
MutationAssessor
Pathogenic
3.4
M;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-3.5
D;.;.;D;D;D
REVEL
Pathogenic
0.83
Sift
Pathogenic
0.0
D;.;.;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D
Polyphen
1.0
D;D;D;.;D;.
Vest4
0.95
MutPred
0.90
Gain of glycosylation at S691 (P = 0.0752);.;.;.;.;.;
MVP
0.93
MPC
0.92
ClinPred
0.99
D
GERP RS
4.5
Varity_R
0.83
gMVP
0.85

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: rs1232358687; hg19: chr4-66230905; API