Genetic Variant EPHA4:c.*1446G>A (chr2-221419926-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004438.5(EPHA4):c.*1446G>A 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 152,576 control chromosomes in the GnomAD database, including 16,761 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 ( 16716 hom., cov: 33)

Exomes 𝑓: 0.41 ( 45 hom. )

Consequence

EPHA4
NM_004438.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.20

Publications

5 publications found

Variant links:

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

EPHA4 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EPHA4	NM_004438.5	MANE Select	c.*1446G>A	3_prime_UTR	Exon 18 of 18	NP_004429.1
EPHA4	NM_001304536.2		c.*1446G>A	3_prime_UTR	Exon 19 of 19	NP_001291465.1
EPHA4	NM_001363748.2		c.*1586G>A	3_prime_UTR	Exon 18 of 18	NP_001350677.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPHA4	ENST00000281821.7	TSL:1 MANE Select	c.*1446G>A		3_prime_UTR	Exon 18 of 18	ENSP00000281821.2
	EPHA4	ENST00000469354.1	TSL:2	n.994G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.460

AC:

69960

AN:

151934

Hom.:

16705

Cov.:

show subpopulations

Gnomad AFR

AF:

0.583

Gnomad AMI

AF:

0.446

Gnomad AMR

AF:

0.391

Gnomad ASJ

AF:

0.390

Gnomad EAS

AF:

0.277

Gnomad SAS

AF:

0.465

Gnomad FIN

AF:

0.454

Gnomad MID

AF:

0.497

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.446

GnomAD4 exome

AF:

0.412

AC:

216

AN:

524

Hom.:

Cov.:

AF XY:

0.437

AC XY:

139

AN XY:

318

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.405

AC:

184

AN:

454

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AF:

0.300

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.460

AC:

69999

AN:

152052

Hom.:

16716

Cov.:

AF XY:

0.462

AC XY:

34320

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.583

AC:

24172

AN:

41448

American (AMR)

AF:

0.390

AC:

5967

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.390

AC:

1354

AN:

3468

East Asian (EAS)

AF:

0.276

AC:

1431

AN:

5180

South Asian (SAS)

AF:

0.464

AC:

2235

AN:

4812

European-Finnish (FIN)

AF:

0.454

AC:

4794

AN:

10560

Middle Eastern (MID)

AF:

0.493

AC:

144

AN:

292

European-Non Finnish (NFE)

AF:

0.420

AC:

28562

AN:

67980

Other (OTH)

AF:

0.441

AC:

933

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1922

3844

5767

7689

9611

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

642

1284

1926

2568

3210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.433

Hom.:

23679

Bravo

AF:

0.458

Asia WGS

AF:

0.380

AC:

1324

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.3

(source)

DANN

Benign

0.74

PhyloP100

-1.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over