1-155063931-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000368409.8(EFNA4):​c.108C>A​(p.Asn36Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,403,430 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

EFNA4
ENST00000368409.8 missense

Scores

8
9
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.86
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EFNA4NM_005227.3 linkuse as main transcriptc.108C>A p.Asn36Lys missense_variant 1/4 ENST00000368409.8 NP_005218.1
EFNA4-EFNA3NM_001407761.1 linkuse as main transcriptc.108C>A p.Asn36Lys missense_variant 1/5 NP_001394690.1
DCST1-AS1NR_040773.1 linkuse as main transcriptn.61G>T non_coding_transcript_exon_variant 1/4
ADAM15-EFNA4NR_176418.1 linkuse as main transcriptn.3426C>A non_coding_transcript_exon_variant 22/26

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EFNA4ENST00000368409.8 linkuse as main transcriptc.108C>A p.Asn36Lys missense_variant 1/41 NM_005227.3 ENSP00000357394 P52798-1
EFNA4ENST00000359751.8 linkuse as main transcriptc.108C>A p.Asn36Lys missense_variant 1/41 ENSP00000352789 P2P52798-2
EFNA4ENST00000427683.2 linkuse as main transcriptc.108C>A p.Asn36Lys missense_variant 1/42 ENSP00000414378 A2P52798-3

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
7.13e-7
AC:
1
AN:
1403430
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
694974
show subpopulations
Gnomad4 AFR exome
AF:
0.0000332
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 12, 2023In 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. 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 disruptive. This variant has not been reported in the literature in individuals affected with EFNA4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 36 of the EFNA4 protein (p.Asn36Lys). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;.;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;M;M;.
MutationTaster
Benign
1.0
D;D;D;D
PROVEAN
Pathogenic
-5.1
D;D;D;D
REVEL
Pathogenic
0.89
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0070
D;D;D;D
Polyphen
1.0
D;P;.;.
Vest4
0.67
MutPred
0.74
Gain of methylation at N36 (P = 0.0157);Gain of methylation at N36 (P = 0.0157);Gain of methylation at N36 (P = 0.0157);Gain of methylation at N36 (P = 0.0157);
MVP
0.98
MPC
1.5
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.89
gMVP
0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-155036407; API