rs10498111

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000281821.7(EPHA4):​c.1875A>T​(p.Lys625Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K625K) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EPHA4
ENST00000281821.7 missense

Scores

2
7
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.20
Variant links:
Genes affected
EPHA4 (HGNC:3388): (EPH receptor A4) 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. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), EPHA4. . Gene score misZ 2.8852 (greater than the threshold 3.09). Trascript score misZ 4.018 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EPHA4NM_004438.5 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 10/18 ENST00000281821.7 NP_004429.1
EPHA4NM_001304536.2 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 11/19 NP_001291465.1
EPHA4NM_001363748.2 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 10/18 NP_001350677.1
EPHA4NM_001304537.2 linkuse as main transcriptc.1722A>T p.Lys574Asn missense_variant 9/17 NP_001291466.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EPHA4ENST00000281821.7 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 10/181 NM_004438.5 ENSP00000281821 P1P54764-1
EPHA4ENST00000409854.5 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 10/171 ENSP00000386276
EPHA4ENST00000409938.5 linkuse as main transcriptc.1875A>T p.Lys625Asn missense_variant 11/182 ENSP00000386829 P1P54764-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251300
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461296
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
726968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.74
BayesDel_addAF
Benign
-0.011
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;.;T
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.82
T;T;.
M_CAP
Benign
0.029
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Benign
-0.51
T
MutationAssessor
Benign
1.4
L;.;L
MutationTaster
Benign
4.8e-8
P;P;P;P
PrimateAI
Pathogenic
0.84
D
PROVEAN
Benign
-2.0
N;N;N
REVEL
Benign
0.23
Sift
Uncertain
0.0020
D;D;D
Sift4G
Benign
0.085
T;T;T
Polyphen
0.87
P;.;P
Vest4
0.56
MutPred
0.56
Loss of methylation at K625 (P = 0.0228);Loss of methylation at K625 (P = 0.0228);Loss of methylation at K625 (P = 0.0228);
MVP
0.57
MPC
1.6
ClinPred
0.80
D
GERP RS
4.8
Varity_R
0.47
gMVP
0.77

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: rs10498111; hg19: chr2-222308226; API