2-221418561-T-C

Variant names:

• chr2-221418561-T-C
• rs3087584
• NM_004438.5:c.*2811A>G

Variant summary

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

The NM_004438.5(EPHA4):​c.*2811A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 152,534 control chromosomes in the GnomAD database, including 16,833 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 0.46 (16796 hom., cov: 33)
  • Exomes 𝑓: 0.43 (37 hom.)
• Consequence: EPHA4 NM_004438.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376
• Publications: 5 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: Illumina, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.581 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.*2811A>G		3_prime_UTR	Exon 18 of 18	NP_004429.1	P54764-1
	EPHA4	NM_001304536.2		c.*2811A>G		3_prime_UTR	Exon 19 of 19	NP_001291465.1	P54764-1
	EPHA4	NM_001363748.2		c.*2951A>G		3_prime_UTR	Exon 18 of 18	NP_001350677.1	E9PG71

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA4	ENST00000281821.7	TSL:1 MANE Select	c.*2811A>G		3_prime_UTR	Exon 18 of 18	ENSP00000281821.2	P54764-1
	EPHA4	ENST00000469354.1	TSL:2	n.2359A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70000 AN: 151988 Hom.: 16779 Cov.: 33

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.451

GnomAD4 exome AF: 0.425 AC: 182 AN: 428 Hom.: 37 Cov.: 0 AF XY: 0.450 AC XY: 116 AN XY: 258

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.421 AC: 176 AN: 418

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 2 AN: 4

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.460 AC: 70041 AN: 152106 Hom.: 16796 Cov.: 33 AF XY: 0.462 AC XY: 34342 AN XY: 74378

African (AFR) AF: 0.588 AC: 24367 AN: 41472

American (AMR) AF: 0.389 AC: 5945 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1348 AN: 3472

East Asian (EAS) AF: 0.242 AC: 1251 AN: 5174

South Asian (SAS) AF: 0.464 AC: 2240 AN: 4828

European-Finnish (FIN) AF: 0.453 AC: 4796 AN: 10580

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.421 AC: 28600 AN: 67984

Other (OTH) AF: 0.446 AC: 942 AN: 2114

Alfa AF: 0.429 Hom.: 17442

Bravo AF: 0.459

Asia WGS AF: 0.359 AC: 1251 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	13
DANN	Benign	0.78
PhyloP100		0.38
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: rs3087584; hg19: chr2-222283281;