19-42248499-G-A

Variant names:

• chr19-42248499-G-A
• NM_006494.4:c.1613C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006494.4(ERF):​c.1613C>T​(p.Thr538Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,360,682 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ERF NM_006494.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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]

ENSG00000268643 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32954594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4	c.1613C>T	p.Thr538Met	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.1613C>T	p.Thr538Met	missense_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.22+6479C>T		intron_variant	Intron 1 of 4	3		ENSP00000470087.1
ERF	ENST00000440177.6	c.1388C>T	p.Thr463Met	missense_variant	Exon 4 of 4	2		ENSP00000388173.2
ENSG00000268643	ENST00000676949.1	n.30+91C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1360682 Hom.: 0 Cov.: 32 AF XY: 0.00000150 AC XY: 1 AN XY: 666798

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: 0.00000188

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Mar 09, 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	0.63
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.45
MutPred		0.27		Gain of helix (P = 0.0425);.;
MVP		0.27
MPC		1.6
ClinPred		0.82	D
GERP RS		4.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.21
gMVP		0.58

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: chr19-42752651;