dbSNP rs2278107: EPHA7:p.Ile138Val (chr6-93410921-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_004440.4(EPHA7):c.412A>G(p.Ile138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,988 control chromosomes in the GnomAD database, including 1,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.035 ( 170 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1631 hom. )

Consequence

EPHA7
NM_004440.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.07

Publications

26 publications found

Variant links:

Genes affected

EPHA7 (HGNC:3390): (EPH receptor A7) 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. Increased expression of this gene is associated with multiple forms of carcinoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]

EPHA7 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 (MetaRNN=0.0017443001).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPHA7	NM_004440.4 link	c.412A>G	p.Ile138Val	missense_variant	Exon 3 of 17	ENST00000369303.9	NP_004431.1	Q15375-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPHA7	ENST00000369303.9 link	c.412A>G	p.Ile138Val	missense_variant	Exon 3 of 17	1	NM_004440.4	ENSP00000358309.4		Q15375-1

Frequencies

GnomAD3 genomes

AF:

0.0354

AC:

5385

AN:

152174

Hom.:

170

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00753

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0704

Gnomad ASJ

AF:

0.0170

Gnomad EAS

AF:

0.168

Gnomad SAS

AF:

0.0606

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0335

Gnomad OTH

AF:

0.0474

GnomAD2 exomes

AF:

0.0527

AC:

13231

AN:

251136

AF XY:

0.0508

show subpopulations

Gnomad AFR exome

AF:

0.00714

Gnomad AMR exome

AF:

0.0946

Gnomad ASJ exome

AF:

0.0146

Gnomad EAS exome

AF:

0.171

Gnomad FIN exome

AF:

0.0347

Gnomad NFE exome

AF:

0.0333

Gnomad OTH exome

AF:

0.0473

GnomAD4 exome

AF:

0.0392

AC:

57329

AN:

1461696

Hom.:

1631

Cov.:

AF XY:

0.0396

AC XY:

28809

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00580

AC:

194

AN:

33442

American (AMR)

AF:

0.0913

AC:

4080

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

405

AN:

26112

East Asian (EAS)

AF:

0.153

AC:

6075

AN:

39700

South Asian (SAS)

AF:

0.0581

AC:

5013

AN:

86252

European-Finnish (FIN)

AF:

0.0363

AC:

1937

AN:

53410

Middle Eastern (MID)

AF:

0.0279

AC:

161

AN:

5766

European-Non Finnish (NFE)

AF:

0.0331

AC:

36805

AN:

1111932

Other (OTH)

AF:

0.0440

AC:

2659

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3256

6512

9767

13023

16279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1478

2956

4434

5912

7390

<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:

0.0354

AC:

5387

AN:

152292

Hom.:

170

Cov.:

AF XY:

0.0370

AC XY:

2759

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00751

AC:

312

AN:

41570

American (AMR)

AF:

0.0704

AC:

1077

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0170

AC:

AN:

3472

East Asian (EAS)

AF:

0.166

AC:

860

AN:

5168

South Asian (SAS)

AF:

0.0611

AC:

295

AN:

4830

European-Finnish (FIN)

AF:

0.0364

AC:

387

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0335

AC:

2281

AN:

68018

Other (OTH)

AF:

0.0502

AC:

106

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

262

524

785

1047

1309

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0370

Hom.:

736

Bravo

AF:

0.0363

TwinsUK

AF:

0.0321

AC:

119

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.0299

AC:

257

ExAC

AF:

0.0498

AC:

6040

Asia WGS

AF:

0.0960

AC:

331

AN:

3478

EpiCase

AF:

0.0331

EpiControl

AF:

0.0315

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.060

T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.1

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.086

Sift

Benign

0.12

T;T

Sift4G

Benign

0.47

T;T

Polyphen

0.010

B;B

Vest4

0.10

MPC

0.32

ClinPred

0.018

GERP RS

4.3

Varity_R

0.18

gMVP

0.36

Mutation Taster

=97/3

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