19-42249565-G-A

Variant names:

• chr19-42249565-G-A
• rs587777006
• NM_006494.4:c.547C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006494.4(ERF):​c.547C>T​(p.Arg183*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ERF NM_006494.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.55
• Publications: 4 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 18 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 25 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42249565-G-A is Pathogenic according to our data. Variant chr19-42249565-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006494.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	NM_006494.4	MANE Select	c.547C>T	p.Arg183*	stop_gained	Exon 4 of 4	NP_006485.2
	ERF	NM_001440421.1		c.-261C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 3	NP_001427350.1
	ERF	NM_001301035.2		c.322C>T	p.Arg108*	stop_gained	Exon 4 of 4	NP_001287964.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	ENST00000222329.9	TSL:1 MANE Select	c.547C>T	p.Arg183*	stop_gained	Exon 4 of 4	ENSP00000222329.3
	ERF	ENST00000595448.1	TSL:1	n.520C>T		non_coding_transcript_exon	Exon 2 of 2
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+5413C>T		intron	N/A	ENSP00000470087.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461244 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111968

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00210 Hom.: 0

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TWIST1-related craniosynostosis Pathogenic:1

Dec 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.Gly299Argfs*9) have been determined to be pathogenic (PMID: 23354439). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 55923). This premature translational stop signal has been observed in individual(s) with clinical features of ERF-related conditions (PMID: 23354439). 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.Arg183*) in the ERF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 366 amino acid(s) of the ERF protein.

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 variant is predicted to result in a premature stop codon at position 183 in ERF, and is absent in gnomAD 4.1. 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: 30758909; ClinVar variant ID: 55923) PVS1, PM2, PM6, PP5

not provided Pathogenic:1

Apr 05, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 366 amino acids are lost, 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: 30758909, 35982159, 23354439, 34184330)

Craniosynostosis 4 Pathogenic:1

Mar 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Craniosynostosis 4;C4310679:Chitayat syndrome Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		2.6
Vest4		0.97
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs587777006; hg19: chr19-42753717;