Variant chr2-73291851-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001965.4(EGR4):c.1067C>G(p.Ala356Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000042 in 1,427,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A356E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

EGR4
NM_001965.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.115026206).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR4	NM_001965.4 linkuse as main transcript	c.1067C>G	p.Ala356Gly	missense_variant	2/2	ENST00000436467.4
EGR4	XM_047443603.1 linkuse as main transcript	c.1064C>G	p.Ala355Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR4	ENST00000436467.4 linkuse as main transcript	c.1067C>G	p.Ala356Gly	missense_variant	2/2	1	NM_001965.4	P2
EGR4	ENST00000545030.1 linkuse as main transcript	c.1376C>G	p.Ala459Gly	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000107

AC:

AN:

186070

Hom.:

AF XY:

0.0000194

AC XY:

AN XY:

103338

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:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000420

AC:

AN:

1427186

Hom.:

Cov.:

AF XY:

0.00000423

AC XY:

AN XY:

708474

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:

0.00000545

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000859

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2023

The c.1376C>G (p.A459G) alteration is located in exon 2 (coding exon 2) of the EGR4 gene. This alteration results from a C to G substitution at nucleotide position 1376, causing the alanine (A) at amino acid position 459 to be replaced by a glycine (G). 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

-0.28

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

.;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.62

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.44

.;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.11

Sift

Uncertain

0.017

D;D

Sift4G

Benign

0.24

T;T

Vest4

0.097

MVP

0.57

MPC

0.50

ClinPred

0.26

GERP RS

3.1

Varity_R

0.11

gMVP

0.41

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