rs587777007
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_006494.4(ERF):c.891_892del(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
NM_006494.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.18
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 5 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 [Likely_pathogenic]. Clinvar id is 55924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERF | NM_006494.4 | c.891_892del | p.Gly299ArgfsTer9 | frameshift_variant | 4/4 | ENST00000222329.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERF | ENST00000222329.9 | c.891_892del | p.Gly299ArgfsTer9 | frameshift_variant | 4/4 | 1 | NM_006494.4 | P1 | |
ERF | ENST00000440177.6 | c.666_667del | p.Gly224ArgfsTer9 | frameshift_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461262Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726936
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Craniosynostosis 4 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 15, 2020 | 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. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 01, 2018 | - - |
TWIST1-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2022 | 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. This variant is not present in population databases (gnomAD no frequency). 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. ClinVar contains an entry for this variant (Variation ID: 55924). 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. For these reasons, this variant has been classified as Pathogenic. - |
See cases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli | Apr 26, 2021 | PVS1_strong;PP5_strong;PM2_supporting - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2022 | 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) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at