1-155066749-G-C

Position:

chr1-155066749-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000368409.8(EFNA4):c.133G>C(p.Val45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,602,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 0 hom. )

Consequence

EFNA4
ENST00000368409.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.226

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 made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12008497).

BS2

High AC in GnomAd4 at 57 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EFNA4	NM_005227.3 linkuse as main transcript	c.133G>C	p.Val45Leu	missense_variant	2/4	ENST00000368409.8	NP_005218.1
EFNA4-EFNA3	NM_001407761.1 linkuse as main transcript	c.113+2813G>C		intron_variant			NP_001394690.1
ADAM15-EFNA4	NR_176418.1 linkuse as main transcript	n.3570G>C		non_coding_transcript_exon_variant	24/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EFNA4	ENST00000368409.8 linkuse as main transcript	c.133G>C	p.Val45Leu	missense_variant	2/4	1	NM_005227.3	ENSP00000357394		P52798-1
EFNA4	ENST00000359751.8 linkuse as main transcript	c.133G>C	p.Val45Leu	missense_variant	2/4	1		ENSP00000352789	P2	P52798-2
EFNA4	ENST00000427683.2 linkuse as main transcript	c.133G>C	p.Val45Leu	missense_variant	2/4	2		ENSP00000414378	A2	P52798-3

Frequencies

GnomAD3 genomes

AF:

0.000375

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000273

AC:

AN:

238062

Hom.:

AF XY:

0.000286

AC XY:

AN XY:

129376

show subpopulations

Gnomad AFR exome

AF:

0.000188

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000284

Gnomad NFE exome

AF:

0.000520

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000305

AC:

442

AN:

1450024

Hom.:

Cov.:

AF XY:

0.000326

AC XY:

235

AN XY:

721446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000240

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000227

Gnomad4 NFE exome

AF:

0.000377

Gnomad4 OTH exome

AF:

0.000184

GnomAD4 genome

AF:

0.000374

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000463

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000280

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

The c.133G>C (p.V45L) alteration is located in exon 2 (coding exon 2) of the EFNA4 gene. This alteration results from a G to C substitution at nucleotide position 133, causing the valine (V) at amino acid position 45 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 45 of the EFNA4 protein (p.Val45Leu). This variant is present in population databases (rs142249822, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EFNA4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2281424). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.49

T;.;.

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.61

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Uncertain

-0.17

MutationAssessor

Benign

0.60

N;N;N

MutationTaster

Benign

1.0

D;N;N;N

PROVEAN

Benign

-0.76

N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.20

T;T;T

Polyphen

0.0060

B;B;.

Vest4

0.17

MutPred

0.51

Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);Gain of sheet (P = 0.1451);

MVP

0.84

MPC

0.51

ClinPred

0.043

GERP RS

4.3

Varity_R

0.048

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over