2-73291713-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001965.4(EGR4):​c.1205G>T​(p.Arg402Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000442 in 1,605,652 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: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

EGR4
NM_001965.4 missense

Scores

6
8
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.13
Variant links:
Genes affected
EGR4 (HGNC:3241): (early growth response 4) Enables DNA-binding transcription activator activity, RNA polymerase II-specific and sequence-specific double-stranded DNA binding activity. Involved in positive regulation of transcription by RNA polymerase II. Predicted to be located in nucleoplasm. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EGR4NM_001965.4 linkc.1205G>T p.Arg402Leu missense_variant Exon 2 of 2 ENST00000436467.4 NP_001956.4 Q05215B7ZKU3
EGR4XM_047443603.1 linkc.1202G>T p.Arg401Leu missense_variant Exon 2 of 2 XP_047299559.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EGR4ENST00000436467.4 linkc.1205G>T p.Arg402Leu missense_variant Exon 2 of 2 1 NM_001965.4 ENSP00000419687.1 A0A0C4DG96
EGR4ENST00000545030.1 linkc.1514G>T p.Arg505Leu missense_variant Exon 2 of 2 1 ENSP00000445626.1 Q05215

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
152018
Hom.:
0
Cov.:
33
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000883
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000165
AC:
4
AN:
242828
Hom.:
0
AF XY:
0.00000757
AC XY:
1
AN XY:
132110
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:
0.0000357
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000447
AC:
65
AN:
1453634
Hom.:
0
Cov.:
32
AF XY:
0.0000401
AC XY:
29
AN XY:
723584
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:
0.0000585
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
152018
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74248
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000883
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000336
Hom.:
0
Bravo
AF:
0.0000189
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.0000247
AC:
3

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1514G>T (p.R505L) alteration is located in exon 2 (coding exon 2) of the EGR4 gene. This alteration results from a G to T substitution at nucleotide position 1514, causing the arginine (R) at amino acid position 505 to be replaced by a leucine (L). 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
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.075
D
BayesDel_noAF
Benign
-0.13
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
.;D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.064
D
MetaRNN
Pathogenic
0.76
D;D
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.4
.;L
PrimateAI
Pathogenic
0.93
D
PROVEAN
Pathogenic
-7.0
D;D
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Vest4
0.85
MVP
0.74
MPC
1.6
ClinPred
0.99
D
GERP RS
4.8
Varity_R
0.87
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs146218927; hg19: chr2-73518841; API