rs587778281
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000122.2(ERCC3):c.1421_1422insA(p.Asp474GlufsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000985 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00010 ( 0 hom. )
Consequence
ERCC3
NM_000122.2 frameshift
NM_000122.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.01
Genes affected
ERCC3 (HGNC:3435): (ERCC excision repair 3, TFIIH core complex helicase subunit) This gene encodes an ATP-dependent DNA helicase that functions in nucleotide excision repair. The encoded protein is a subunit of basal transcription factor 2 (TFIIH) and, therefore, also functions in class II transcription. Mutations in this gene are associated with Xeroderma pigmentosum B, Cockayne's syndrome, and trichothiodystrophy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-127280552-A-AT is Pathogenic according to our data. Variant chr2-127280552-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 134130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC3 | NM_000122.2 | c.1421_1422insA | p.Asp474GlufsTer2 | frameshift_variant | 9/15 | ENST00000285398.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC3 | ENST00000285398.7 | c.1421_1422insA | p.Asp474GlufsTer2 | frameshift_variant | 9/15 | 1 | NM_000122.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152232Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
10
AN:
152232
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251350Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135840
GnomAD3 exomes
AF:
AC:
19
AN:
251350
Hom.:
AF XY:
AC XY:
8
AN XY:
135840
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000102 AC: 149AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000102 AC XY: 74AN XY: 727236
GnomAD4 exome
AF:
AC:
149
AN:
1461868
Hom.:
Cov.:
32
AF XY:
AC XY:
74
AN XY:
727236
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000657 AC: 10AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74376
GnomAD4 genome
?
AF:
AC:
10
AN:
152232
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74376
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2023 | This sequence change creates a premature translational stop signal (p.Asp474Glufs*2) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs587778281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosa (PMID: 16947863). ClinVar contains an entry for this variant (Variation ID: 134130). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 03, 2023 | Frameshift 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; Also known as c.1421_1422insA; This variant is associated with the following publications: (PMID: 26971583, 27356891, 31589614, 30414346, 29625052, 34308104, 24728327, 36451132, 36493725, 16947863) - |
Xeroderma pigmentosum group B Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 08, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
Xeroderma pigmentosum Pathogenic:1
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 23, 2022 | - - |
Xeroderma pigmentosum group B;C4225344:Trichothiodystrophy 2, photosensitive Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
not specified Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at