rs587777007

Variant names:

• chr19-42249219-CCT-C
• rs587777007
• NM_006494.4:c.891_892delAG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_006494.4(ERF):​c.891_892delAG​(p.Gly299ArgfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,262 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ERF NM_006494.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.18
• Publications: 7 publications found

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

ENSG00000268643 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42249219-CCT-C is Pathogenic according to our data. Variant chr19-42249219-CCT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 55924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERF	NM_006494.4	c.891_892delAG	p.Gly299ArgfsTer9	frameshift_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.891_892delAG	p.Gly299ArgfsTer9	frameshift_variant	Exon 4 of 4	1	NM_006494.4	ENSP00000222329.3
ENSG00000268643	ENST00000594664.1	c.22+5757_22+5758delAG		intron_variant	Intron 1 of 4	3		ENSP00000470087.1
ERF	ENST00000440177.6	c.666_667delAG	p.Gly224ArgfsTer9	frameshift_variant	Exon 4 of 4	2		ENSP00000388173.2
ERF	ENST00000715593.1	c.*80_*81delAG		3_prime_UTR_variant	Exon 3 of 3			ENSP00000520487.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461262 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726936

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111754

Other (OTH) AF: 0.00 AC: 0 AN: 60338

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Craniosynostosis 4 Pathogenic:3

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 15, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This ERF variant is absent in a large population dataset. It has been identified in three unrelated families with complex craniosynostosis and has an entry in ClinVar. This frameshift variant is predicted to lead to a premature stop codon in the last exon of the gene, likely escaping nonsense-mediated decay and resulting in a truncated protein product. We consider it to be likely pathogenic. -

Aug 07, 2024

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Information summarized from clinical sequencing report: The c.891_892del (p.G299Rfs*9) variant in the ERF gene has been previously reported in multiple unrelated families with craniosynostosis (PMID: 23354439, 30758909, 36360262). It has been observed in gnomAD (v4) at a low frequency. This frameshift variant is located in exon 4 of 4. It is predicted to escape nonsense-mediated decay (NMD) but impact a significant portion of the protein length (250aa, 46% of the protein) or a critical region of the protein, potentially disrupting normal protein function. -

Inborn genetic diseases Pathogenic:1

Oct 01, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TWIST1-related craniosynostosis Pathogenic:1

Apr 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with clinical features of ERF-related craniosynostosis (PMID: 28808027, 30758909). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly299Argfs*9) in the ERF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 250 amino acid(s) of the ERF protein. ClinVar contains an entry for this variant (Variation ID: 55924). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ERF protein in which other variant(s) (p.Pro358Thrfs*20) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. -

Noonan-like syndrome Pathogenic:1

Jan 10, 2025

Department of Medical Genetics, Tohoku University School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This frameshift variant is predicted to result in a premature stop codon in ERF, and is observed in gnomAD 4.1 at a low frequency. This variant has been identified as a de novo occurrence, without confirmation of paternity and maternity. This variant has been reported in multiple symptomatic individuals (PMID: 23354439, 30758909, 36360262; ClinVar variant ID: 55924). PVS1, PM6, PP5 -

See cases Pathogenic:1

Apr 26, 2021

Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_strong;PP5_strong;PM2_supporting -

Chitayat syndrome Pathogenic:1

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation, as the last 250 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23354439, 30758909) -

Craniosynostosis 4;C4310679:Chitayat syndrome Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1_Strong+PS4_Moderate+PM6+PP1+PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777007; hg19: chr19-42753371;