19-42248550-G-C

Variant names:

• chr19-42248550-G-C
• NM_006494.4:c.1562C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006494.4(ERF):​c.1562C>G​(p.Ala521Gly) 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. 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)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.289

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]

ENSG00000268643 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067341715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4	c.1562C>G	p.Ala521Gly	missense_variant	Exon 4 of 4	ENST00000222329.9	NP_006485.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERF	ENST00000222329.9	c.1562C>G	p.Ala521Gly	missense_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.22+6428C>G		intron_variant	Intron 1 of 4	3		ENSP00000470087.1
ERF	ENST00000440177.6	c.1337C>G	p.Ala446Gly	missense_variant	Exon 4 of 4	2		ENSP00000388173.2
ENSG00000268643	ENST00000676949.1	n.30+40C>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1562C>G (p.A521G) alteration is located in exon 4 (coding exon 4) of the ERF gene. This alteration results from a C to G substitution at nucleotide position 1562, causing the alanine (A) at amino acid position 521 to be replaced by a glycine (G). 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	0.057
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.067	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.31	N;N
REVEL	Benign	0.052
Sift	Benign	0.12	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0020	B;.
Vest4		0.19
MutPred		0.13		Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.30
MPC		0.66
ClinPred		0.049	T
GERP RS		4.4
Varity_R		0.078
gMVP		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: chr19-42752702;