Genetic Variant NM_004438.5: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:

Genome browser will be placed here

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
EPHA4	NM_004438.5 link	c.*1446G>A	3_prime_UTR_variant	Exon 18 of 18	ENST00000281821.7	NP_004429.1	P54764-1A1MA61
EPHA4	NM_001304536.2 link	c.*1446G>A	3_prime_UTR_variant	Exon 19 of 19		NP_001291465.1	P54764-1A1MA61
EPHA4	NM_001363748.2 link	c.*1586G>A	3_prime_UTR_variant	Exon 18 of 18		NP_001350677.1
EPHA4	NM_001304537.2 link	c.*1446G>A	3_prime_UTR_variant	Exon 17 of 17		NP_001291466.1	P54764-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA4	ENST00000281821.7 link	c.*1446G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_004438.5	ENSP00000281821.2		P54764-1
EPHA4	ENST00000469354.1 link	n.994G>A		non_coding_transcript_exon_variant	Exon 2 of 2	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 v4.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over