rs879255259
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003401.5(XRCC4):c.760del(p.Asp254MetfsTer66) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000206 in 1,454,356 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: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
XRCC4
NM_003401.5 frameshift
NM_003401.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.13
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 5-83258543-AG-A is Pathogenic according to our data. Variant chr5-83258543-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208522.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-83258543-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRCC4 | NM_003401.5 | c.760del | p.Asp254MetfsTer66 | frameshift_variant | 7/8 | ENST00000396027.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC4 | ENST00000396027.9 | c.760del | p.Asp254MetfsTer66 | frameshift_variant | 7/8 | 5 | NM_003401.5 | A1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 0.0000206 AC: 30AN: 1454356Hom.: 0 Cov.: 31 AF XY: 0.0000263 AC XY: 19AN XY: 723262
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31
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19
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723262
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2021 | 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. Studies have shown that this premature translational stop signal alters XRCC4 gene expression (PMID: 26255102). ClinVar contains an entry for this variant (Variation ID: 208522). This premature translational stop signal has been observed in individual(s) with clinical features of XRCC4-related conditions (PMID: 26255102). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asp254Metfs*68) in the XRCC4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 83 amino acid(s) of the XRCC4 protein. - |
Short stature, microcephaly, and endocrine dysfunction Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 23, 2015 | - - |
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