NM_004438.5:c.2074+239G>T

Variant names:

• chr2-221442590-C-A
• rs2288629
• NM_004438.5:c.2074+239G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004438.5(EPHA4):​c.2074+239G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.812 in 152,084 control chromosomes in the GnomAD database, including 50,281 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.81 (50281 hom., cov: 32)
• Consequence: EPHA4 NM_004438.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.614
• Publications: 4 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004438.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA4	NM_004438.5	MANE Select	c.2074+239G>T		intron	N/A	NP_004429.1
	EPHA4	NM_001304536.2		c.2074+239G>T		intron	N/A	NP_001291465.1
	EPHA4	NM_001363748.2		c.2074+239G>T		intron	N/A	NP_001350677.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA4	ENST00000281821.7	TSL:1 MANE Select	c.2074+239G>T		intron	N/A	ENSP00000281821.2
	EPHA4	ENST00000409854.5	TSL:1	c.2074+239G>T		intron	N/A	ENSP00000386276.1
	EPHA4	ENST00000409938.5	TSL:2	c.2074+239G>T		intron	N/A	ENSP00000386829.1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123341 AN: 151966 Hom.: 50244 Cov.: 32

Gnomad AFR AF: 0.759

Gnomad AMI AF: 0.759

Gnomad AMR AF: 0.826

Gnomad ASJ AF: 0.785

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.907

Gnomad FIN AF: 0.832

Gnomad MID AF: 0.769

Gnomad NFE AF: 0.820

Gnomad OTH AF: 0.803

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.812 AC: 123433 AN: 152084 Hom.: 50281 Cov.: 32 AF XY: 0.814 AC XY: 60488 AN XY: 74354

African (AFR) AF: 0.759 AC: 31473 AN: 41458

American (AMR) AF: 0.826 AC: 12628 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.785 AC: 2726 AN: 3472

East Asian (EAS) AF: 0.981 AC: 5077 AN: 5176

South Asian (SAS) AF: 0.906 AC: 4370 AN: 4824

European-Finnish (FIN) AF: 0.832 AC: 8804 AN: 10578

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.820 AC: 55739 AN: 67980

Other (OTH) AF: 0.806 AC: 1698 AN: 2108

Alfa AF: 0.812 Hom.: 140859

Bravo AF: 0.807

Asia WGS AF: 0.933 AC: 3240 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.68
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism (auto)

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: rs2288629; hg19: chr2-222307310;