19-42248669-C-G

Variant names:

• chr19-42248669-C-G
• NM_006494.4:c.1443G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_006494.4(ERF):​c.1443G>C​(p.Lys481Asn) 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. 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: -0.970

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a cross_link Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2) (size 0) in uniprot entity ERF_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22574028).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4	c.1443G>C	p.Lys481Asn	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.1443G>C	p.Lys481Asn	missense_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.22+6309G>C		intron_variant	Intron 1 of 4	3		ENSP00000470087.1
ERF	ENST00000440177.6	c.1218G>C	p.Lys406Asn	missense_variant	Exon 4 of 4	2		ENSP00000388173.2
ENSG00000268643	ENST00000676949.1	n.-50G>C		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 04, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.14	B;.
Vest4		0.48
MutPred		0.47		Loss of methylation at K481 (P = 0.0121);.;
MVP		0.43
MPC		1.6
ClinPred		0.92	D
GERP RS		0.85
Varity_R		0.32
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-42752821;