3-89407322-G-C
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The ENST00000336596.7(EPHA3):āc.1648G>Cā(p.Ala550Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000992 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000010 ( 0 hom. )
Consequence
EPHA3
ENST00000336596.7 missense
ENST00000336596.7 missense
Scores
4
9
6
Clinical Significance
Conservation
PhyloP100: 6.53
Genes affected
EPHA3 (HGNC:3387): (EPH receptor A3) 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. This gene encodes a protein that binds ephrin-A ligands. Two alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.9
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
EPHA3 | NM_005233.6 | c.1648G>C | p.Ala550Pro | missense_variant | 8/17 | ENST00000336596.7 | NP_005224.2 | |
EPHA3 | NM_001410778.1 | c.1648G>C | p.Ala550Pro | missense_variant | 8/17 | NP_001397707.1 | ||
EPHA3 | XM_005264715.4 | c.1645G>C | p.Ala549Pro | missense_variant | 8/17 | XP_005264772.1 | ||
EPHA3 | XM_047447673.1 | c.1645G>C | p.Ala549Pro | missense_variant | 8/17 | XP_047303629.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
EPHA3 | ENST00000336596.7 | c.1648G>C | p.Ala550Pro | missense_variant | 8/17 | 1 | NM_005233.6 | ENSP00000337451 | P1 | |
EPHA3 | ENST00000494014.1 | c.1648G>C | p.Ala550Pro | missense_variant | 8/17 | 1 | ENSP00000419190 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461386Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726994
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74286
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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 submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | The c.1648G>C (p.A550P) alteration is located in exon 8 (coding exon 8) of the EPHA3 gene. This alteration results from a G to C substitution at nucleotide position 1648, causing the alanine (A) at amino acid position 550 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MutPred
Loss of stability (P = 0.021);Loss of stability (P = 0.021);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at