2-221426597-G-T

Position:

chr2-221426597-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2

The NM_004438.5(EPHA4):c.2713C>A(p.Pro905Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

EPHA4
NM_004438.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.99

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.32851815).

BS2

High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EPHA4	NM_004438.5 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	16/18	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	17/19		NP_001291465.1
EPHA4	NM_001363748.2 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	16/18		NP_001350677.1
EPHA4	NM_001304537.2 linkuse as main transcript	c.2560C>A	p.Pro854Thr	missense_variant	15/17		NP_001291466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	16/18	1	NM_004438.5	ENSP00000281821	P1	P54764-1
EPHA4	ENST00000409854.5 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	16/17	1		ENSP00000386276
EPHA4	ENST00000409938.5 linkuse as main transcript	c.2713C>A	p.Pro905Thr	missense_variant	17/18	2		ENSP00000386829	P1	P54764-1
EPHA4	ENST00000424339.1 linkuse as main transcript	c.*17C>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	2		ENSP00000408145

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250546

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135428

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:

0.0000705

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461478

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727004

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:

0.0000234

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Nov 09, 2021

The c.2713C>A (p.P905T) alteration is located in exon 16 (coding exon 16) of the EPHA4 gene. This alteration results from a C to A substitution at nucleotide position 2713, causing the proline (P) at amino acid position 905 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.034

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Benign

0.91

DEOGEN2

Benign

0.23

T;.;T

Eigen

Benign

0.075

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;D;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Benign

-0.54

MutationAssessor

Benign

0.45

N;.;N

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.15

N;N;N

REVEL

Benign

0.14

Sift

Benign

0.30

T;T;T

Sift4G

Benign

0.83

T;T;T

Polyphen

0.038

B;.;B

Vest4

0.59

MVP

0.67

MPC

0.64

ClinPred

0.18

GERP RS

5.8

Varity_R

0.16

gMVP

0.71

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over