Genetic Variant EFNA4:p.Tyr94Asp (chr1-155066896-T-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_005227.3(EFNA4):c.280T>G(p.Tyr94Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

EFNA4
NM_005227.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.34

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.32339603).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFNA4	NM_005227.3 link	c.280T>G	p.Tyr94Asp	missense_variant	Exon 2 of 4	ENST00000368409.8	NP_005218.1	P52798-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EFNA4	ENST00000368409.8 link	c.280T>G	p.Tyr94Asp	missense_variant	Exon 2 of 4	1	NM_005227.3	ENSP00000357394.3	P52798-1
EFNA4	ENST00000359751.8 link	c.280T>G	p.Tyr94Asp	missense_variant	Exon 2 of 4	1		ENSP00000352789.4	P52798-2
EFNA4-EFNA3	ENST00000505139.1 link	c.113+2960T>G		intron_variant	Intron 1 of 4	2		ENSP00000426741.1	B4DXG7
EFNA4	ENST00000427683.2 link	c.280T>G	p.Tyr94Asp	missense_variant	Exon 2 of 4	2		ENSP00000414378.2	P52798-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251266

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727190

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.280T>G (p.Y94D) alteration is located in exon 2 (coding exon 2) of the EFNA4 gene. This alteration results from a T to G substitution at nucleotide position 280, causing the tyrosine (Y) at amino acid position 94 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.68

T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Uncertain

-0.26

MutationAssessor

Benign

0.0

N;N;N

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Uncertain

0.36

Sift

Uncertain

0.016

D;D;T

Sift4G

Uncertain

0.022

D;D;D

Polyphen

0.86

P;B;.

Vest4

0.34

MutPred

0.51

Gain of ubiquitination at K95 (P = 0.0581);Gain of ubiquitination at K95 (P = 0.0581);Gain of ubiquitination at K95 (P = 0.0581);

MVP

0.95

MPC

0.90

ClinPred

0.65

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.51

gMVP

0.49

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