Genetic Variant EGR4:p.Ala356Val (chr2-73291851-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001965.4(EGR4):c.1067C>T(p.Ala356Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000633 in 1,579,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

EGR4
NM_001965.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.27

Publications

0 publications found

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:

ENSG00000310032 (HGNC:):

ENSG00000310032 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06317794).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001965.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR4	NM_001965.4	MANE Select	c.1067C>T	p.Ala356Val	missense	Exon 2 of 2	NP_001956.4	A0A0C4DG96

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGR4	ENST00000436467.4	TSL:1 MANE Select	c.1067C>T	p.Ala356Val	missense	Exon 2 of 2	ENSP00000419687.1	A0A0C4DG96
EGR4	ENST00000545030.1	TSL:1	c.1376C>T	p.Ala459Val	missense	Exon 2 of 2	ENSP00000445626.1	Q05215
EGR4	ENST00000858695.1		c.1064C>T	p.Ala355Val	missense	Exon 2 of 2	ENSP00000528754.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152162

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000269

AC:

AN:

186070

AF XY:

0.00000968

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000676

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000667

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000418

GnomAD4 exome

AF:

0.00000561

AC:

AN:

1427186

Hom.:

Cov.:

AF XY:

0.00000565

AC XY:

AN XY:

708474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32684

American (AMR)

AF:

0.0000733

AC:

AN:

40920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24912

East Asian (EAS)

AF:

0.00

AC:

AN:

38582

South Asian (SAS)

AF:

0.00

AC:

AN:

82662

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.00000273

AC:

AN:

1100490

Other (OTH)

AF:

0.0000338

AC:

AN:

59104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

M_CAP

Benign

0.0083

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

PhyloP100

2.3

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.55

REVEL

Benign

0.045

Sift

Benign

0.081

Sift4G

Benign

0.42

Vest4

0.062

MVP

0.41

MPC

0.50

ClinPred

0.049

GERP RS

3.1

Varity_R

0.048

gMVP

0.43

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over