chr2-73292223-C-G

Position:

• chr2-73292223-C-G

Variant summary

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

The NM_001965.4(EGR4):​c.695G>C​(p.Arg232Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R232C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGR4 NM_001965.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0830

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=0.18312451).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGR4	NM_001965.4	c.695G>C	p.Arg232Pro	missense_variant	2/2	ENST00000436467.4
EGR4	XM_047443603.1	c.692G>C	p.Arg231Pro	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGR4	ENST00000436467.4	c.695G>C	p.Arg232Pro	missense_variant	2/2	1	NM_001965.4	P2
EGR4	ENST00000545030.1	c.1004G>C	p.Arg335Pro	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Mar 15, 2024

The c.1004G>C (p.R335P) alteration is located in exon 2 (coding exon 2) of the EGR4 gene. This alteration results from a G to C substitution at nucleotide position 1004, causing the arginine (R) at amino acid position 335 to be replaced by a proline (P). 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	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;T
Eigen	Benign	-0.084
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.10	N;N
REVEL	Benign	0.12
Sift	Benign	0.059	T;D
Sift4G	Benign	0.28	T;T
Vest4		0.24
MVP		0.70
MPC		1.7
ClinPred		0.63	D
GERP RS		4.2
Varity_R		0.26
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-73519351;