1-155066888-C-T
Variant summary
Our verdict is Uncertain significance. The variant received 1 classification points (ACMG Germline Pathogenicity v2019). PM2BP4
The NM_001407761.1(EFNA4-EFNA3):c.113+2952C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. Note: NM_001407761.1 is not a MANE Select or MANE Plus Clinical transcript for EFNA4-EFNA3; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.00000372 (AC=6) in the gnomAD database across 1,614,034 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
EFNA4-EFNA3
NM_001407761.1 intron
NM_001407761.1 intron
Scores
7
11
Clinical Significance
Conservation
PhyloP100: 1.38
Publications
0 publications found
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 Gene-Disease associations (from GenCC):
- craniosynostosisInheritance: AD Classification: LIMITED Submitted by: PanelApp Australia
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new If you want to explore the variant's impact on the transcript NM_001407761.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.
Classification according to ACMG Germline Pathogenicity v2019
Classification was made for transcript
Our verdict: Uncertain_significance. The variant received 1 points.
PM2
Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
BP4
Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Supporting).
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_001407761.1. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| EFNA4 | TSL:1 MANE Select | c.272C>T | p.Pro91Leu | missense | Exon 2 of 4 | ENSP00000357394.3 | P52798-1 | ||
| EFNA4 | TSL:1 | c.272C>T | p.Pro91Leu | missense | Exon 2 of 4 | ENSP00000352789.4 | P52798-2 | ||
| EFNA4-EFNA3 | TSL:2 | c.113+2952C>T | intron | N/A | ENSP00000426741.1 | K9J7H7 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 32 show subpopulations
GnomAD3 genomes
AF:
AC:
2
AN:
152254
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 727184 show subpopulations
GnomAD4 exome
AF:
AC:
4
AN:
1461780
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
727184
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
AC:
0
AN:
53320
Middle Eastern (MID)
AF:
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
AC:
4
AN:
1112002
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.0000131 AC: 2AN: 152254Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74380 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
GnomAD4 genome
AF:
AC:
2
AN:
152254
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74380
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
AC:
0
AN:
41472
American (AMR)
AF:
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3472
East Asian (EAS)
AF:
AC:
0
AN:
5196
South Asian (SAS)
AF:
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
AC:
2
AN:
68040
Other (OTH)
AF:
AC:
0
AN:
2094
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.400
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
TOPMed (Bravo)
AF:
AC:
1
AN:
264690
Hom.:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)
AF:
AC:
0
AN:
13470
Hom.:
Case/control cohorts
Cohort
Cases
Controls
BipEx
1 / 28420AF: 0.0000351865
0 / 28844AF: 0
SCHEMA
1 / 77664AF: 0.0000128760
0 / 139302AF: 0
Allele count / allele number. AF is computed from the counts for ASC (not provided by the source).
ClinVar
ClinVar submissions
View on ClinVar Significance:Uncertain significance
Revision:criteria provided, single submitter
Pathogenic
VUS
Benign
Condition
-
1
-
not specified (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Benign
T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
PhyloP100
PROVEAN
Benign
N
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.
Publications
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Other links and lift over
dbSNP: rs1407731922 ;
hg19: chr1-155039364;