rs121434324
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000082.4(ERCC8):c.37G>T(p.Glu13Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000458 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000046 ( 0 hom. )
Consequence
ERCC8
NM_000082.4 stop_gained
NM_000082.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 2.45
Genes affected
ERCC8 (HGNC:3439): (ERCC excision repair 8, CSA ubiquitin ligase complex subunit) This gene encodes a WD repeat protein, which interacts with Cockayne syndrome type B (CSB) protein and with p44 protein, a subunit of the RNA polymerase II transcription factor IIH. Mutations in this gene have been identified in patients with hereditary disease Cockayne syndrome (CS). CS cells are abnormally sensitive to ultraviolet radiation and are defective in the repair of transcriptionally active genes. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 75 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 5-60944972-C-A is Pathogenic according to our data. Variant chr5-60944972-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-60944972-C-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC8 | NM_000082.4 | c.37G>T | p.Glu13Ter | stop_gained | 1/12 | ENST00000676185.1 | |
ERCC8 | NM_001007234.3 | c.37G>T | p.Glu13Ter | stop_gained | 1/6 | ||
ERCC8 | NM_001007233.3 | c.-356G>T | 5_prime_UTR_variant | 1/13 | |||
ERCC8 | NM_001290285.2 | c.-341G>T | 5_prime_UTR_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC8 | ENST00000676185.1 | c.37G>T | p.Glu13Ter | stop_gained | 1/12 | NM_000082.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152150Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000755 AC: 19AN: 251494Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135922
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GnomAD4 exome AF: 0.0000458 AC: 67AN: 1461866Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727236
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152150Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3AN XY: 74342
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25333069, 29572252, 29742419, 14661080, 15744458, 19894250) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Glu13*) in the ERCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC8 are known to be pathogenic (PMID: 29572252). This variant is present in population databases (rs121434324, gnomAD 0.1%). This premature translational stop signal has been observed in individuals with Cockayne syndrome (PMID: 14661080, 29572252). ClinVar contains an entry for this variant (Variation ID: 1716). For these reasons, this variant has been classified as Pathogenic. - |
Cockayne syndrome type 1 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 06, 2020 | NM_000082.3(ERCC8):c.37G>T(E13*) is classified as pathogenic in the context of ERCC8-related disorders. Sources cited for classification include the following: PMID 19894250 and 14661080. Classification of NM_000082.3(ERCC8):c.37G>T(E13*) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 03, 2020 | The p.Glu13X variant in ERCC8 has been reported in 2 compound heterozygous and 3 homozgyous individuals with Cockayne syndrome (Cao 2004 PMID:14661080, Laugel 2010 PMID: 19894250, Calmels 2018 PMID: 29572252). It has been identified in 0.139% (14/10080) of Ashkenazi Jewish chromosomes and 0.004% of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). It is also reported in ClinVar (Variation ID: 1716). This nonsense variant leads to a premature termination codon at position 13, which is predicted to lead to a truncated or absent protein. Loss of function of the ERCC8 gene is an established disease mechanism in autosomal recessive Cockayne syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Cockayne syndrome. ACMG/AMP Criteria applied: PVS1_Strong, PM3_Strong. - |
Cockayne syndrome type 1;C3553298:UV-sensitive syndrome 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 14, 2021 | - - |
Cockayne syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2020 | Variant summary: ERCC8 c.37G>T (p.Glu13X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.6e-05 in 251494 control chromosomes (gnomAD). c.37G>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Cockayne Syndrome (Cao_2004, Ridley_2005, Nardo_2009, Calmels_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of protein product and greatly decreased cell survival after UV irradiation in patient derived fibroblasts (Ridley_2005, Nardo_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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