4-65404419-C-T

Variant names:

• chr4-65404419-C-T
• rs1057520012
• NM_001281766.3:c.1748G>A

Variant summary

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

The NM_001281765.3(EPHA5):​c.1748G>A​(p.Gly583Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPHA5 NM_001281765.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.76
• Publications: 4 publications found

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

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001281765.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA5	NM_001281766.3	MANE Select	c.1748G>A	p.Gly583Glu	missense	Exon 8 of 17	NP_001268695.1
	EPHA5	NM_001281765.3		c.1748G>A	p.Gly583Glu	missense	Exon 8 of 18	NP_001268694.1
	EPHA5	NM_004439.8		c.1745G>A	p.Gly582Glu	missense	Exon 8 of 18	NP_004430.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA5	ENST00000613740.5	TSL:1 MANE Select	c.1748G>A	p.Gly583Glu	missense	Exon 8 of 17	ENSP00000478537.1
	EPHA5	ENST00000622150.4	TSL:1	c.1748G>A	p.Gly583Glu	missense	Exon 8 of 18	ENSP00000480763.1
	EPHA5	ENST00000273854.7	TSL:1	c.1745G>A	p.Gly582Glu	missense	Exon 8 of 18	ENSP00000273854.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.055	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.015	D
Polyphen		0.97	D
Vest4		0.69
MutPred		0.65		Gain of sheet (P = 0.0344)
MVP		0.60
MPC		0.76
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.95
gMVP		0.76
Mutation Taster		=55/45	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1057520012; hg19: chr4-66270137; COSMIC: COSV56640899;