8-22690538-C-T

Variant names:

• chr8-22690538-C-T
• NM_004430.3:c.1099G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004430.3(EGR3):​c.1099G>A​(p.Gly367Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EGR3 NM_004430.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.821
• Publications: 0 publications found

Genes affected

EGR3 (HGNC:3240): (early growth response 3) This gene encodes a transcriptional regulator that belongs to the EGR family of C2H2-type zinc-finger proteins. It is an immediate-early growth response gene which is induced by mitogenic stimulation. The protein encoded by this gene participates in the transcriptional regulation of genes in controling biological rhythm. It may also play a role in a wide variety of processes including muscle development, lymphocyte development, endothelial cell growth and migration, and neuronal development. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Dec 2010]

EGR3-AS1 (HGNC:58186):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.119620144).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004430.3. 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
	EGR3	NM_004430.3	MANE Select	c.1099G>A	p.Gly367Ser	missense	Exon 2 of 2	NP_004421.2
	EGR3	NM_001199880.2		c.985G>A	p.Gly329Ser	missense	Exon 2 of 2	NP_001186809.1	Q06889-2
	EGR3	NM_001199881.2		c.937G>A	p.Gly313Ser	missense	Exon 2 of 2	NP_001186810.1	B4DH80

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGR3	ENST00000317216.3	TSL:1 MANE Select	c.1099G>A	p.Gly367Ser	missense	Exon 2 of 2	ENSP00000318057.2	Q06889-1
	EGR3	ENST00000522910.1	TSL:2	c.985G>A	p.Gly329Ser	missense	Exon 2 of 2	ENSP00000430310.1	Q06889-2
	EGR3	ENST00000519492.1	TSL:5	c.*936G>A		3_prime_UTR	Exon 3 of 3	ENSP00000429370.1	E5RIM5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461080 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726834

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52786

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.077
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.82
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.076
Sift	Benign	0.068	T
Sift4G	Benign	0.44	T
Polyphen		0.10	B
Vest4		0.11
MutPred		0.36		Gain of phosphorylation at G367 (P = 0.0068)
MVP		0.56
ClinPred		0.37	T
GERP RS		5.6
Varity_R		0.086
gMVP		0.80
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

hg19: chr8-22548051; COSMIC: COSV57833028; COSMIC: COSV57833028;