8-22692301-C-A

Position:

• chr8-22692301-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_Moderate BS2

The NM_001199880.2(EGR3):​c.40+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,366,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EGR3 NM_001199880.2 splice_donor, intron
• Scores: Splicing: ADA: 0.9022
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.03

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]

ENSG00000253125 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.05904762 fraction of the gene.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGR3	NM_004430.3	c.154+490G>T		intron_variant		ENST00000317216.3	NP_004421.2
EGR3	NM_001199880.2	c.40+1G>T		splice_donor_variant, intron_variant			NP_001186809.1
EGR3	NM_001199881.2	c.-9+198G>T		intron_variant			NP_001186810.1
EGR3	XM_011544429.3	c.40+1G>T		splice_donor_variant, intron_variant			XP_011542731.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGR3	ENST00000317216.3	c.154+490G>T		intron_variant		1	NM_004430.3	ENSP00000318057.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000117 AC: 16 AN: 1366700 Hom.: 0 Cov.: 34 AF XY: 0.0000119 AC XY: 8 AN XY: 674514

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: 0.0000301

Gnomad4 NFE exome AF: 0.0000112

Gnomad4 OTH exome AF: 0.0000526

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EGR3-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2023

The EGR3 c.40+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	0.11
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.80	D
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.90
dbscSNV1_RF	Benign	0.72
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

Other links and lift over

dbSNP: rs1403960253; hg19: chr8-22549814;