2-221536366-G-T

Variant names:

• chr2-221536366-G-T
• rs16862811
• NM_004438.5:c.823+27365C>A

Variant summary

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

The NM_004438.5(EPHA4):​c.823+27365C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,148 control chromosomes in the GnomAD database, including 1,078 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 0.11 (1078 hom., cov: 32)
• Consequence: EPHA4 NM_004438.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.823
• 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: Illumina, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 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.823+27365C>A		intron	N/A	NP_004429.1	P54764-1
	EPHA4	NM_001304536.2		c.823+27365C>A		intron	N/A	NP_001291465.1	P54764-1
	EPHA4	NM_001363748.2		c.823+27365C>A		intron	N/A	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.823+27365C>A		intron	N/A	ENSP00000281821.2	P54764-1
	EPHA4	ENST00000409854.5	TSL:1	c.823+27365C>A		intron	N/A	ENSP00000386276.1	E9PG71
	EPHA4	ENST00000409938.5	TSL:2	c.823+27365C>A		intron	N/A	ENSP00000386829.1	P54764-1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16329 AN: 152030 Hom.: 1077 Cov.: 32

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0822

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.107 AC: 16331 AN: 152148 Hom.: 1078 Cov.: 32 AF XY: 0.107 AC XY: 7962 AN XY: 74376

African (AFR) AF: 0.0457 AC: 1899 AN: 41522

American (AMR) AF: 0.0820 AC: 1253 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 408 AN: 3464

East Asian (EAS) AF: 0.150 AC: 779 AN: 5180

South Asian (SAS) AF: 0.0723 AC: 348 AN: 4814

European-Finnish (FIN) AF: 0.178 AC: 1884 AN: 10572

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9395 AN: 68000

Other (OTH) AF: 0.110 AC: 233 AN: 2112

Alfa AF: 0.123 Hom.: 3429

Bravo AF: 0.0982

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.66
PhyloP100		-0.82
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: rs16862811; hg19: chr2-222401086;