rs121913047
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000122.2(ERCC3):c.1273C>T(p.Arg425Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,996 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R425R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000122.2 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC3 | NM_000122.2 | c.1273C>T | p.Arg425Ter | stop_gained | 8/15 | ENST00000285398.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC3 | ENST00000285398.7 | c.1273C>T | p.Arg425Ter | stop_gained | 8/15 | 1 | NM_000122.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251402Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461880Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4AN XY: 727240
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74312
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 16585). This premature translational stop signal has been observed in individual(s) with ERCC3-related conditions (PMID: 16947863, 26884178). This variant is present in population databases (rs121913047, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Arg425*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 11, 2023 | Reported in trans with a second ERCC3 variant in two sisters with features of xeroderma pigmentosa (Oh et al., 2006); Published functions studies demonstrate a damaging effect resulting in defective DNA repair activity (Oh et al., 2006); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 20947453, 26884178, 28588253, 29376097, 27004399, 19199647, 16947863, 26689913, 29625052) - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2022 | The c.1273C>T (p.R425*) alteration, located in exon 8 (coding exon 8) of the ERCC3 gene, consists of a C to T substitution at nucleotide position 1273. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 425. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (2/251402) total alleles studied. The highest observed frequency was <0.01% (2/113682) of European (non-Finnish) alleles. This alteration has been reported along with a second ERCC3 alteration in patients with features of ERCC3-related spectrum disorders (Garcia-Moreno, 2018; Oh, 2006). Functional studies show that this alteration leads to greatly reduced activity compared to wild type (Oh, 2006). Based on the available evidence, this alteration is classified as pathogenic. - |
Trichothiodystrophy 2, photosensitive Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 06, 2024 | - - |
Xeroderma pigmentosum group B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2006 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at