Genetic Variant EGR4:p.Lys453Asn (chr2-73291559-C-G) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001965.4(EGR4):c.1359G>C(p.Lys453Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,613,448 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: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

EGR4
NM_001965.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.476

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]

EGR4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30484688).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGR4	NM_001965.4 link	c.1359G>C	p.Lys453Asn	missense_variant	Exon 2 of 2	ENST00000436467.4	NP_001956.4	Q05215B7ZKU3
EGR4	XM_047443603.1 link	c.1356G>C	p.Lys452Asn	missense_variant	Exon 2 of 2		XP_047299559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGR4	ENST00000436467.4 link	c.1359G>C	p.Lys453Asn	missense_variant	Exon 2 of 2	1	NM_001965.4	ENSP00000419687.1		A0A0C4DG96
EGR4	ENST00000545030.1 link	c.1668G>C	p.Lys556Asn	missense_variant	Exon 2 of 2	1		ENSP00000445626.1		Q05215

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

248106

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134558

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:

0.00000897

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461244

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726964

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:

0.0000432

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1668G>C (p.K556N) alteration is located in exon 2 (coding exon 2) of the EGR4 gene. This alteration results from a G to C substitution at nucleotide position 1668, causing the lysine (K) at amino acid position 556 to be replaced by an asparagine (N). 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

1.0

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

.;D

Eigen

Benign

-0.028

Eigen_PC

Benign

-0.055

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.94

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.12

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0080

D;D

Vest4

0.39

MVP

0.63

MPC

1.4

ClinPred

0.98

GERP RS

0.93

Varity_R

0.77

gMVP

0.78

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