2-221420645-G-C

Variant names:

• chr2-221420645-G-C
• rs13386128
• NM_004438.5:c.*820-93C>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.*820-93C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 152,116 control chromosomes in the GnomAD database, including 2,323 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 0.16 (2323 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: EPHA4 NM_004438.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.02
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA4	NM_004438.5	c.*820-93C>G		intron_variant	Intron 17 of 17	ENST00000281821.7	NP_004429.1
EPHA4	NM_001304536.2	c.*820-93C>G		intron_variant	Intron 18 of 18		NP_001291465.1
EPHA4	NM_001363748.2	c.*960-93C>G		intron_variant	Intron 17 of 17		NP_001350677.1
EPHA4	NM_001304537.2	c.*820-93C>G		intron_variant	Intron 16 of 16		NP_001291466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7	c.*820-93C>G		intron_variant	Intron 17 of 17	1	NM_004438.5	ENSP00000281821.2
EPHA4	ENST00000469354.1	n.368-93C>G		intron_variant	Intron 1 of 1	2
EPHA4	ENST00000472696.1	n.424-93C>G		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25071 AN: 151998 Hom.: 2315 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0375

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.0835

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.171

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

GnomAD4 genome AF: 0.165 AC: 25098 AN: 152116 Hom.: 2323 Cov.: 33 AF XY: 0.162 AC XY: 12082 AN XY: 74368

African (AFR) AF: 0.221 AC: 9162 AN: 41488

American (AMR) AF: 0.131 AC: 2009 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 727 AN: 3468

East Asian (EAS) AF: 0.0374 AC: 194 AN: 5188

South Asian (SAS) AF: 0.214 AC: 1030 AN: 4816

European-Finnish (FIN) AF: 0.0835 AC: 884 AN: 10590

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10546 AN: 67970

Other (OTH) AF: 0.169 AC: 356 AN: 2110

Alfa AF: 0.0460 Hom.: 51

Bravo AF: 0.168

Asia WGS AF: 0.118 AC: 410 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.037
DANN	Benign	0.53
PhyloP100		-1.0
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: rs13386128; hg19: chr2-222285365;