Genetic Variant EPHA4:c.1716-3840A>G (chr2-221450021-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004438.5(EPHA4):c.1716-3840A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0555 in 152,298 control chromosomes in the GnomAD database, including 462 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 0.055 ( 462 hom., cov: 33)

Consequence

EPHA4
NM_004438.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.12

Publications

1 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: Illumina, Ambry Genetics

EPHA4 links:

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new If you want to explore the variant's impact on the transcript NM_004438.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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	UniProt
EPHA4	NM_004438.5	MANE Select	c.1716-3840A>G	intron	N/A	NP_004429.1	P54764-1
EPHA4	NM_001304536.2		c.1716-3840A>G	intron	N/A	NP_001291465.1	P54764-1
EPHA4	NM_001363748.2		c.1716-3840A>G	intron	N/A	NP_001350677.1	E9PG71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EPHA4	ENST00000281821.7	TSL:1 MANE Select	c.1716-3840A>G	intron	N/A	ENSP00000281821.2	P54764-1
EPHA4	ENST00000409854.5	TSL:1	c.1716-3840A>G	intron	N/A	ENSP00000386276.1	E9PG71
EPHA4	ENST00000409938.5	TSL:2	c.1716-3840A>G	intron	N/A	ENSP00000386829.1	P54764-1

Frequencies

GnomAD3 genomes

AF:

0.0554

AC:

8424

AN:

152180

Hom.:

460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0764

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.0905

Gnomad SAS

AF:

0.0710

Gnomad FIN

AF:

0.00593

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.0488

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

GnomAD4 genome

AF:

0.0555

AC:

8450

AN:

152298

Hom.:

462

Cov.:

AF XY:

0.0560

AC XY:

4173

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.138

AC:

5736

AN:

41544

American (AMR)

AF:

0.0765

AC:

1170

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0429

AC:

149

AN:

3472

East Asian (EAS)

AF:

0.0909

AC:

471

AN:

5180

South Asian (SAS)

AF:

0.0703

AC:

339

AN:

4824

European-Finnish (FIN)

AF:

0.00593

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00607

AC:

413

AN:

68026

Other (OTH)

AF:

0.0482

AC:

102

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

393

786

1180

1573

1966

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

282

376

470

<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:

0.0316

Hom.:

Bravo

AF:

0.0660

Asia WGS

AF:

0.0850

AC:

297

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.6

(source)

DANN

Benign

0.48

PhyloP100

1.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over