rs1555750816

Variant names:

• chr19-42249544-TAC-T
• rs1555750816
• NM_006494.4:c.566_567delGT

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.566_567delGT​(p.Cys189fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERF NM_006494.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.58
• Publications: 0 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 24 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-42249544-TAC-T is Pathogenic according to our data. Variant chr19-42249544-TAC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 543070.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.566_567delGT	p.Cys189fs	frameshift	Exon 4 of 4	NP_006485.2
	ERF	NM_001301035.2		c.341_342delGT	p.Cys114fs	frameshift	Exon 4 of 4	NP_001287964.1
	ERF	NM_001308402.2		c.341_342delGT	p.Cys114fs	frameshift	Exon 4 of 4	NP_001295331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERF	ENST00000222329.9	TSL:1 MANE Select	c.566_567delGT	p.Cys189fs	frameshift	Exon 4 of 4	ENSP00000222329.3
	ERF	ENST00000595448.1	TSL:1	n.539_540delGT		non_coding_transcript_exon	Exon 2 of 2
	ENSG00000268643	ENST00000594664.1	TSL:3	c.22+5432_22+5433delGT		intron	N/A	ENSP00000470087.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TWIST1-related craniosynostosis Pathogenic:1

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Cys189*) in the ERF gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 360 amino acid(s) of the ERF protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ERF-related conditions. ClinVar contains an entry for this variant (Variation ID: 543070). 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. For these reasons, this variant has been classified as Pathogenic.

Craniosynostosis 4 Pathogenic:1

Jun 05, 2020

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=3/197	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: rs1555750816; hg19: chr19-42753696;