Genetic Variant NM_006494.4:c.1244C>G (chr19-42248868-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006494.4(ERF):c.1244C>G(p.Ala415Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A415V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

ERF
NM_006494.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0350

Publications

4 publications found

Variant links:

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]

ERF Gene-Disease associations (from GenCC):

Chitayat syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
craniosynostosis 4
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, ClinGen, Genomics England PanelApp
Crouzon syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
isolated scaphocephaly
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ERF links:

ENSG00000268643 (HGNC:):

ENSG00000268643 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06690663).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4 link	c.1244C>G	p.Ala415Gly	missense_variant	Exon 4 of 4	ENST00000222329.9	NP_006485.2	P50548-1A0A024R0L4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERF	ENST00000222329.9 link	c.1244C>G	p.Ala415Gly	missense_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3		P50548-1
ENSG00000268643	ENST00000594664.1 link	c.22+6110C>G		intron_variant	Intron 1 of 4	3		ENSP00000470087.1		M0QYV0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1455034

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723628

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33416

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.00

AC:

AN:

86010

European-Finnish (FIN)

AF:

0.0000204

AC:

AN:

49136

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110370

Other (OTH)

AF:

0.0000166

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.412

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

1.3

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.11

T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.53

T;T

M_CAP

Benign

0.0067

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;.

PhyloP100

-0.035

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.14

N;N

REVEL

Benign

0.066

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.54

T;T

Polyphen

0.16

B;.

Vest4

0.044

MutPred

0.11

Loss of helix (P = 0.079);.;

MVP

0.10

MPC

0.64

ClinPred

0.13

GERP RS

2.9

Varity_R

0.063

gMVP

0.10

Mutation Taster

=90/10

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over