Genetic Variant EFNA4:p.His60Tyr (chr1-155066794-C-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_005227.3(EFNA4):c.178C>T(p.His60Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00216 in 1,612,736 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H60R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 10 hom. )

Consequence

EFNA4
NM_005227.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 4.68

Publications

9 publications found

Variant links:

Genes affected

EFNA4 (HGNC:3224): (ephrin A4) 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 that has been implicated in proliferation and metastasis of several types of cancers. [provided by RefSeq, May 2022]

EFNA4 links:

EFNA4-EFNA3 (HGNC:):

EFNA4-EFNA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3530325).

BP6

Variant 1-155066794-C-T is Benign according to our data. Variant chr1-155066794-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1554935.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 205 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005227.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EFNA4	NM_005227.3	MANE Select	c.178C>T	p.His60Tyr	missense	Exon 2 of 4	NP_005218.1
EFNA4	NM_182689.2		c.178C>T	p.His60Tyr	missense	Exon 2 of 4	NP_872631.1
EFNA4	NM_182690.3		c.178C>T	p.His60Tyr	missense	Exon 2 of 4	NP_872632.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EFNA4	ENST00000368409.8	TSL:1 MANE Select	c.178C>T	p.His60Tyr	missense	Exon 2 of 4	ENSP00000357394.3
EFNA4	ENST00000359751.8	TSL:1	c.178C>T	p.His60Tyr	missense	Exon 2 of 4	ENSP00000352789.4
EFNA4-EFNA3	ENST00000505139.1	TSL:2	c.113+2858C>T		intron	N/A	ENSP00000426741.1

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00217

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00131

AC:

327

AN:

249144

AF XY:

0.00149

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000731

Gnomad ASJ exome

AF:

0.000202

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00204

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00225

AC:

3285

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00220

AC XY:

1599

AN XY:

726590

show subpopulations

African (AFR)

AF:

0.000330

AC:

AN:

33302

American (AMR)

AF:

0.000744

AC:

AN:

44344

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26032

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00179

AC:

154

AN:

86076

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00573

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00265

AC:

2951

AN:

1111550

Other (OTH)

AF:

0.00157

AC:

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

191

381

572

762

953

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.00135

AC:

205

AN:

152366

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74518

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41582

American (AMR)

AF:

0.00189

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00218

AC:

148

AN:

68038

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00145

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00146

AC:

177

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00311

EpiControl

AF:

0.00302

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.069

BayesDel_noAF

Uncertain

0.12

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.35

MetaSVM

Uncertain

0.67

MutationAssessor

Uncertain

2.5

PhyloP100

4.7

PROVEAN

Pathogenic

-5.1

REVEL

Pathogenic

0.72

Sift

Benign

0.039

Sift4G

Uncertain

0.035

Polyphen

1.0

Vest4

0.84

MVP

0.97

MPC

1.5

ClinPred

0.098

GERP RS

5.3

Varity_R

0.62

gMVP

0.56

Mutation Taster

=38/62

disease causing

(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