19-42248868-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006494.4(ERF):c.1244C>T(p.Ala415Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0174 in 1,607,218 control chromosomes in the GnomAD database, including 276 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A415A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 13 hom., cov: 32)

Exomes 𝑓: 0.018 ( 263 hom. )

Consequence

ERF
NM_006494.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002723068).

BP6

Variant 19-42248868-G-A is Benign according to our data. Variant chr19-42248868-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 476625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0117 (1781/152190) while in subpopulation NFE AF = 0.0182 (1240/67964). AF 95% confidence interval is 0.0174. There are 13 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1781 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4 link	c.1244C>T	p.Ala415Val	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>T	p.Ala415Val	missense_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3		P50548-1
ENSG00000268643	ENST00000594664.1 link	c.22+6110C>T		intron_variant	Intron 1 of 4	3		ENSP00000470087.1		M0QYV0

Frequencies

GnomAD3 genomes

AF:

0.0117

AC:

1781

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00312

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00791

Gnomad SAS

AF:

0.00705

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0182

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.0140

AC:

3275

AN:

233218

AF XY:

0.0142

show subpopulations

Gnomad AFR exome

AF:

0.00363

Gnomad AMR exome

AF:

0.00562

Gnomad ASJ exome

AF:

0.00614

Gnomad EAS exome

AF:

0.00568

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0206

Gnomad OTH exome

AF:

0.0126

GnomAD4 exome

AF:

0.0180

AC:

26133

AN:

1455028

Hom.:

263

Cov.:

AF XY:

0.0177

AC XY:

12820

AN XY:

723626

show subpopulations

African (AFR)

AF:

0.00287

AC:

AN:

33416

American (AMR)

AF:

0.00586

AC:

261

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00658

AC:

171

AN:

25996

East Asian (EAS)

AF:

0.0136

AC:

537

AN:

39612

South Asian (SAS)

AF:

0.00982

AC:

845

AN:

86010

European-Finnish (FIN)

AF:

0.0191

AC:

938

AN:

49132

Middle Eastern (MID)

AF:

0.00279

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0201

AC:

22331

AN:

1110368

Other (OTH)

AF:

0.0156

AC:

938

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

1588

3176

4763

6351

7939

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

854

1708

2562

3416

4270

<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

AF:

0.0117

AC:

1781

AN:

152190

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

868

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00311

AC:

129

AN:

41528

American (AMR)

AF:

0.00634

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00792

AC:

AN:

5174

South Asian (SAS)

AF:

0.00705

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0193

AC:

205

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1240

AN:

67964

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

163

245

326

408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00303

AC:

ESP6500EA

AF:

0.0169

AC:

141

ExAC

AF:

0.0152

AC:

1834

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.0159

EpiControl

AF:

0.0138

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 07, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

TWIST1-related craniosynostosis

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.7

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.098

T;.

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0027

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.

PhyloP100

-0.035

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.11

N;N

REVEL

Benign

0.071

Sift

Benign

0.36

T;T

Sift4G

Benign

0.78

T;T

Polyphen

0.0010

B;.

Vest4

0.020

MPC

0.63

ClinPred

0.0038

GERP RS

2.9

Varity_R

0.031

gMVP

0.11

Mutation Taster

=97/3

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over