rs587777008
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_006494.4(ERF):c.256C>T(p.Arg86Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R86H) has been classified as Uncertain significance.
Frequency
Consequence
NM_006494.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERF | NM_006494.4 | c.256C>T | p.Arg86Cys | missense_variant, splice_region_variant | 2/4 | ENST00000222329.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERF | ENST00000222329.9 | c.256C>T | p.Arg86Cys | missense_variant, splice_region_variant | 2/4 | 1 | NM_006494.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461414Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727020
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Craniosynostosis 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Same nucleotide change resulting in same amino acid change has been previously reported as de novoo in similarly affected unrelated individual and observed in at least two similarly affected unrelated individuals (ClinVar ID: VCV000055925.4, PMID:23354439, PS2, PS4_M). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.765, 3Cnet: 0.950, PP3). Patient's phenotype is considered compatible with Craniosynostosis 4 (3billion dataset, PP4). Therefore, this variant is classified likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Jun 29, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2013 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | ERF: PM1, PM2, PM6, PS4:Moderate, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2023 | Published functional studies demonstrate a damaging effect with failure to repress ETS binding site-containing promoters (Twigg et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28160402, 27738187, 32901917, 35852485, 35952322, 23354439) - |
TWIST1-related craniosynostosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 04, 2019 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported to affect ERF protein function (PMID:23354439). This variant has been observed to be de novo in individuals affected with craniosynostosis (PMID: 23354439). ClinVar contains an entry for this variant (Variation ID: 55925). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 86 of the ERF protein (p.Arg86Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. - |
ERF-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 04, 2023 | The ERF c.256C>T variant is predicted to result in the amino acid substitution p.Arg86Cys. This variant was reported as de novo and inherited from an affected father in two apparently unrelated individuals with craniosynostosis (Twigg. 2013. PubMed ID: 23354439; Table S2, Seo. 2020. PubMed ID: 32901917). Variable expressivity and incomplete penetrance has been reported for variants in ERF (Glass. 2019. PubMed ID: 30758909). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at