chr4-65348113-C-T

Position:

• chr4-65348113-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001281766.3(EPHA5):​c.2536G>A​(p.Val846Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHA5 NM_001281766.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

Genes affected

EPHA5 (HGNC:3389): (EPH receptor A5) 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. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Aug 2013]

ACMG classification

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	Protein	UniProt
EPHA5	NM_001281766.3	c.2536G>A	p.Val846Ile	missense_variant	14/17	ENST00000613740.5	NP_001268695.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHA5	ENST00000613740.5	c.2536G>A	p.Val846Ile	missense_variant	14/17	1	NM_001281766.3	ENSP00000478537	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.2599G>A (p.V867I) alteration is located in exon 15 (coding exon 15) of the EPHA5 gene. This alteration results from a G to A substitution at nucleotide position 2599, causing the valine (V) at amino acid position 867 to be replaced by an isoleucine (I). 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	0.21
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T;.;T;.;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.1	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.90	N;.;.;N;N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D;.;.;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D;D;D
Polyphen		1.0	D;D;D;.;D;.
Vest4		0.56
MutPred		0.62		Gain of glycosylation at Y864 (P = 0.076);.;.;.;.;.;
MVP		0.82
MPC		0.71
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.57
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-66213831;