rs752848379

Variant names:

Variant summary

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

The NM_005227.3(EFNA4):c.386C>G(p.Thr129Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,609,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

EFNA4
NM_005227.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.155

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=0.09878188).

BS2

High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EFNA4	NM_005227.3 link	c.386C>G	p.Thr129Ser	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.386C>G	p.Thr129Ser	missense_variant	Exon 2 of 4	1	NM_005227.3	ENSP00000357394.3	P52798-1
EFNA4	ENST00000359751.8 link	c.386C>G	p.Thr129Ser	missense_variant	Exon 2 of 4	1		ENSP00000352789.4	P52798-2
EFNA4-EFNA3	ENST00000505139.1 link	c.113+3066C>G		intron_variant	Intron 1 of 4	2		ENSP00000426741.1	B4DXG7
EFNA4	ENST00000427683.2 link	c.386C>G	p.Thr129Ser	missense_variant	Exon 2 of 4	2		ENSP00000414378.2	P52798-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000567

AC:

AN:

246908

Hom.:

AF XY:

0.0000600

AC XY:

AN XY:

133426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000711

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000898

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000755

AC:

AN:

1457576

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724844

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.386C>G (p.T129S) alteration is located in exon 2 (coding exon 2) of the EFNA4 gene. This alteration results from a C to G substitution at nucleotide position 386, causing the threonine (T) at amino acid position 129 to be replaced by a serine (S). 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

Benign

0.14

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.27

T;.;.

Eigen

Benign

0.045

Eigen_PC

Benign

0.068

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.078

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Uncertain

-0.059

MutationAssessor

Benign

1.1

L;L;L

PROVEAN

Benign

0.48

N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.48

T;T;T

Sift4G

Benign

0.42

T;T;T

Polyphen

0.98

D;P;.

Vest4

0.15

MutPred

0.46

Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);

MVP

0.93

MPC

1.2

ClinPred

0.14

GERP RS

5.3

Varity_R

0.059

gMVP

0.22

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