19-42248547-C-G

Variant summary

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

The NM_006494.4(ERF):c.1565G>C(p.Gly522Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000286 in 1,400,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.66

Genes affected

ERF (HGNC:3444): (ETS2 repressor factor) ETS2 is a transcription factor and protooncogene involved in development, apoptosis, and the regulation of telomerase. The protein encoded by this gene binds to the ETS2 promoter and is a strong repressor of ETS2 transcription. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

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=0.14433596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERF	NM_006494.4	c.1565G>C	p.Gly522Ala	missense_variant	4/4	ENST00000222329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERF	ENST00000222329.9	c.1565G>C	p.Gly522Ala	missense_variant	4/4	1	NM_006494.4	P1
ERF	ENST00000440177.6	c.1340G>C	p.Gly447Ala	missense_variant	4/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1400744 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691774

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: 0.00000369

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2023

The c.1565G>C (p.G522A) alteration is located in exon 4 (coding exon 4) of the ERF gene. This alteration results from a G to C substitution at nucleotide position 1565, causing the glycine (G) at amino acid position 522 to be replaced by an alanine (A). 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	0.065
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.058
Sift	Benign	0.23	T;T
Sift4G	Benign	0.31	T;T
Polyphen		0.46	P;.
Vest4		0.17
MutPred		0.14		Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.48
MPC		0.68
ClinPred		0.19	T
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.070
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1221140466; hg19: chr19-42752699;