chr1-22576499-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_020526.5(EPHA8):c.442A>G(p.Ile148Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
EPHA8
NM_020526.5 missense
NM_020526.5 missense
Scores
1
8
9
Clinical Significance
Conservation
PhyloP100: 6.29
Genes affected
EPHA8 (HGNC:3391): (EPH receptor A8) This gene encodes a member of 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. The protein encoded by this gene functions as a receptor for ephrin A2, A3 and A5 and plays a role in short-range contact-mediated axonal guidance during development of the mammalian nervous system. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EPHA8 | NM_020526.5 | c.442A>G | p.Ile148Val | missense_variant | 3/17 | ENST00000166244.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EPHA8 | ENST00000166244.8 | c.442A>G | p.Ile148Val | missense_variant | 3/17 | 2 | NM_020526.5 | P1 | |
EPHA8 | ENST00000374644.8 | c.442A>G | p.Ile148Val | missense_variant | 3/5 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251398Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135908
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461846Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22AN XY: 727228
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74330
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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 | Apr 19, 2023 | The c.442A>G (p.I148V) alteration is located in exon 3 (coding exon 3) of the EPHA8 gene. This alteration results from a A to G substitution at nucleotide position 442, causing the isoleucine (I) at amino acid position 148 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Uncertain
D;D
Sift4G
Uncertain
T;T
Polyphen
D;D
Vest4
MutPred
Loss of methylation at K144 (P = 0.0911);Loss of methylation at K144 (P = 0.0911);
MVP
MPC
0.73
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