chr2-73292198-A-C

Position:

• chr2-73292198-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001965.4(EGR4):​c.720T>G​(p.Ile240Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,440,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: EGR4 NM_001965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.339

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]

ACMG classification

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=0.06978235).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR4	NM_001965.4	c.720T>G	p.Ile240Met	missense_variant	2/2	ENST00000436467.4
EGR4	XM_047443603.1	c.717T>G	p.Ile239Met	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR4	ENST00000436467.4	c.720T>G	p.Ile240Met	missense_variant	2/2	1	NM_001965.4	P2
EGR4	ENST00000545030.1	c.1029T>G	p.Ile343Met	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1440678 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714724

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: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

The c.1029T>G (p.I343M) alteration is located in exon 2 (coding exon 2) of the EGR4 gene. This alteration results from a T to G substitution at nucleotide position 1029, causing the isoleucine (I) at amino acid position 343 to be replaced by a methionine (M). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.2
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	0.70	N;N
REVEL	Benign	0.023
Sift	Benign	0.18	T;T
Sift4G	Benign	0.36	T;T
Vest4		0.11
MVP		0.51
MPC		1.2
ClinPred		0.25	T
GERP RS		-1.9
Varity_R		0.091
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1689121175; hg19: chr2-73519326;