chr5-83111066-GC-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003401.5(XRCC4):c.179del(p.Ala60GlufsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000686 in 1,458,334 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
XRCC4
NM_003401.5 frameshift
NM_003401.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.66
Genes affected
XRCC4 (HGNC:12831): (X-ray repair cross complementing 4) The protein encoded by this gene functions together with DNA ligase IV and the DNA-dependent protein kinase in the repair of DNA double-strand breaks. This protein plays a role in both non-homologous end joining and the completion of V(D)J recombination. Mutations in this gene can cause short stature, microcephaly, and endocrine dysfunction (SSMED). Alternate transcript variants such as NM_022406 are unlikely to be expressed in some individuals due to a polymorphism (rs1805377) in the last splice acceptor site. [provided by RefSeq, Oct 2019]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 5-83111066-GC-G is Pathogenic according to our data. Variant chr5-83111066-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 1962334.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRCC4 | NM_003401.5 | c.179del | p.Ala60GlufsTer11 | frameshift_variant | 3/8 | ENST00000396027.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC4 | ENST00000396027.9 | c.179del | p.Ala60GlufsTer11 | frameshift_variant | 3/8 | 5 | NM_003401.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
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GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247724Hom.: 0 AF XY: 0.00000746 AC XY: 1AN XY: 134040
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458334Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725466
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with XRCC4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala60Glufs*11) in the XRCC4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in XRCC4 are known to be pathogenic (PMID: 25728776). - |
Computational scores
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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