dbSNP rs10498111: EPHA4:p.Lys625Asn (chr2-221443506-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

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. 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
NM_004438.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.20

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Illumina

EPHA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
EPHA4	NM_004438.5 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 10 of 18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 11 of 19		NP_001291465.1
EPHA4	NM_001363748.2 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 10 of 18		NP_001350677.1
EPHA4	NM_001304537.2 link	c.1722A>T	p.Lys574Asn	missense_variant	Exon 9 of 17		NP_001291466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
EPHA4	ENST00000281821.7 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 10 of 18	1	NM_004438.5	ENSP00000281821.2
EPHA4	ENST00000409854.5 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 10 of 17	1		ENSP00000386276.1
EPHA4	ENST00000409938.5 link	c.1875A>T	p.Lys625Asn	missense_variant	Exon 11 of 18	2		ENSP00000386829.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251300

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111566

Other (OTH)

AF:

0.00

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

(source)

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

PhyloP100

2.2

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

Mutation Taster

=31/69

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over