Variant 2-221443506-T-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004438.5(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.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EPHA4
NM_004438.5 missense

Scores

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]

EPHA4 links:

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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
EPHA4	NM_004438.5 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	10/18	ENST00000281821.7	NP_004429.1	P54764-1A1MA61
EPHA4	NM_001304536.2 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	11/19		NP_001291465.1	P54764-1A1MA61
EPHA4	NM_001363748.2 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	10/18		NP_001350677.1
EPHA4	NM_001304537.2 linkuse as main transcript	c.1722A>T	p.Lys574Asn	missense_variant	9/17		NP_001291466.1	P54764-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EPHA4	ENST00000281821.7 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	10/18	1	NM_004438.5	ENSP00000281821.2	P54764-1
EPHA4	ENST00000409854.5 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	10/17	1		ENSP00000386276.1	E9PG71
EPHA4	ENST00000409938.5 linkuse as main transcript	c.1875A>T	p.Lys625Asn	missense_variant	11/18	2		ENSP00000386829.1	P54764-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251300

Hom.:

AF XY:

0.00

AC XY:

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:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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.:

ExAC

AF:

0.00000824

AC:

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

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

T;T;.

M_CAP

Benign

0.029

MetaRNN

Uncertain

0.54

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.4

L;.;L

PrimateAI

Pathogenic

0.84

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over