rs149364215
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_005236.3(ERCC4):c.2065C>A(p.Arg689Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,852 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R689C) has been classified as Uncertain significance.
Frequency
Consequence
NM_005236.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ERCC4 | NM_005236.3 | c.2065C>A | p.Arg689Ser | missense_variant | 11/11 | ENST00000311895.8 | |
ERCC4 | XM_011522424.4 | c.2203C>A | p.Arg735Ser | missense_variant | 12/12 | ||
ERCC4 | XM_047433774.1 | c.1276C>A | p.Arg426Ser | missense_variant | 8/8 | ||
ERCC4 | XM_011522427.2 | c.715C>A | p.Arg239Ser | missense_variant | 6/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ERCC4 | ENST00000311895.8 | c.2065C>A | p.Arg689Ser | missense_variant | 11/11 | 1 | NM_005236.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251434Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135892
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461852Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727224
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cockayne syndrome;C0268140:Xeroderma pigmentosum, group F;C3808988:Fanconi anemia complementation group Q Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 04, 2019 | This variant has been observed in an individual affected with Fanconi anemia (PMID: 23623386). In this individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 55824). This variant has been reported to affect ERCC4 protein function (PMID: 23623386, 30165384, 28292785, 30658521). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is present in population databases (rs149364215, ExAC 0.003%). This sequence change replaces arginine with serine at codon 689 of the ERCC4 protein (p.Arg689Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. - |
Fanconi anemia complementation group Q Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 02, 2013 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at