rs4745

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004428.3(EFNA1):c.476A>T(p.Asp159Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,502 control chromosomes in the GnomAD database, including 200,789 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D159E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 14138 hom., cov: 31)

Exomes 𝑓: 0.50 ( 186651 hom. )

Consequence

EFNA1
NM_004428.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.349

Publications

68 publications found

Variant links:

Genes affected

EFNA1 (HGNC:3221): (ephrin A1) This gene encodes a member of the ephrin (EPH) family. The ephrins and EPH-related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events, especially in the nervous system and in erythropoiesis. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. This gene encodes an EFNA class ephrin which binds to the EPHA2, EPHA4, EPHA5, EPHA6, and EPHA7 receptors. Two transcript variants that encode different isoforms were identified through sequence analysis. [provided by RefSeq, Jul 2008]

EFNA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.9061713E-5).

BP6

Variant 1-155133751-A-T is Benign according to our data. Variant chr1-155133751-A-T is described in ClinVar as Benign. ClinVar VariationId is 1268289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFNA1	NM_004428.3 link	c.476A>T	p.Asp159Val	missense_variant	Exon 4 of 5	ENST00000368407.8	NP_004419.2	P20827-1
EFNA1	NM_182685.2 link	c.410A>T	p.Asp137Val	missense_variant	Exon 3 of 4		NP_872626.1	P20827-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EFNA1	ENST00000368407.8 link	c.476A>T	p.Asp159Val	missense_variant	Exon 4 of 5	1	NM_004428.3	ENSP00000357392.3		P20827-1

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60864

AN:

151790

Hom.:

14132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.494

Gnomad AMR

AF:

0.384

Gnomad ASJ

AF:

0.588

Gnomad EAS

AF:

0.179

Gnomad SAS

AF:

0.467

Gnomad FIN

AF:

0.518

Gnomad MID

AF:

0.570

Gnomad NFE

AF:

0.527

Gnomad OTH

AF:

0.441

GnomAD2 exomes

AF:

0.447

AC:

112467

AN:

251430

AF XY:

0.463

show subpopulations

Gnomad AFR exome

AF:

0.161

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.585

Gnomad EAS exome

AF:

0.201

Gnomad FIN exome

AF:

0.510

Gnomad NFE exome

AF:

0.533

Gnomad OTH exome

AF:

0.481

GnomAD4 exome

AF:

0.496

AC:

725303

AN:

1461594

Hom.:

186651

Cov.:

AF XY:

0.500

AC XY:

363399

AN XY:

727130

show subpopulations

African (AFR)

AF:

0.157

AC:

5249

AN:

33478

American (AMR)

AF:

0.332

AC:

14839

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.584

AC:

15261

AN:

26130

East Asian (EAS)

AF:

0.143

AC:

5671

AN:

39686

South Asian (SAS)

AF:

0.475

AC:

40932

AN:

86252

European-Finnish (FIN)

AF:

0.510

AC:

27247

AN:

53416

Middle Eastern (MID)

AF:

0.633

AC:

3652

AN:

5768

European-Non Finnish (NFE)

AF:

0.525

AC:

583286

AN:

1111760

Other (OTH)

AF:

0.483

AC:

29166

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

21578

43157

64735

86314

107892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16252

32504

48756

65008

81260

<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:

0.401

AC:

60881

AN:

151908

Hom.:

14138

Cov.:

AF XY:

0.403

AC XY:

29913

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.170

AC:

7028

AN:

41434

American (AMR)

AF:

0.383

AC:

5844

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.588

AC:

2042

AN:

3472

East Asian (EAS)

AF:

0.179

AC:

928

AN:

5178

South Asian (SAS)

AF:

0.469

AC:

2258

AN:

4810

European-Finnish (FIN)

AF:

0.518

AC:

5462

AN:

10542

Middle Eastern (MID)

AF:

0.565

AC:

166

AN:

294

European-Non Finnish (NFE)

AF:

0.527

AC:

35774

AN:

67928

Other (OTH)

AF:

0.443

AC:

932

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1647

3293

4940

6586

8233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

576

1152

1728

2304

2880

<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:

0.506

Hom.:

15334

Bravo

AF:

0.377

TwinsUK

AF:

0.535

AC:

1982

ALSPAC

AF:

0.512

AC:

1972

ESP6500AA

AF:

0.174

AC:

766

ESP6500EA

AF:

0.529

AC:

4547

ExAC

AF:

0.448

AC:

54439

Asia WGS

AF:

0.326

AC:

1133

AN:

3478

EpiCase

AF:

0.549

EpiControl

AF:

0.555

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 09, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29748316, 29083408) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.036

T;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.48

T;T

MetaRNN

Benign

0.000039

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.0

N;.

PhyloP100

-0.35

PrimateAI

Benign

0.28

PROVEAN

Benign

0.67

N;N

REVEL

Benign

0.24

Sift

Benign

0.63

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.0

B;B

Vest4

0.053

MPC

0.27

ClinPred

0.0087

GERP RS

-0.26

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.9

Varity_R

0.11

gMVP

0.32

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over