rs869320677
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_003401.5(XRCC4):c.25del(p.His9ThrfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,613,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00042 ( 0 hom. )
Consequence
XRCC4
NM_003401.5 frameshift
NM_003401.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.869
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 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 5-83104942-TC-T is Pathogenic according to our data. Variant chr5-83104942-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-83104942-TC-T is described in Lovd as [Pathogenic]. Variant chr5-83104942-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr5-83104942-TC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| XRCC4 | NM_003401.5 | c.25del | p.His9ThrfsTer8 | frameshift_variant | 2/8 | ENST00000396027.9 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| XRCC4 | ENST00000396027.9 | c.25del | p.His9ThrfsTer8 | frameshift_variant | 2/8 | 5 | NM_003401.5 | A1 |
Frequencies
GnomAD3 genomes 0.000394 AC: 60AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000394 AC: 99AN: 251062Hom.: 0 AF XY: 0.000405 AC XY: 55AN XY: 135710
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GnomAD4 exome AF: 0.000420 AC: 613AN: 1461012Hom.: 0 Cov.: 30 AF XY: 0.000407 AC XY: 296AN XY: 726850
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GnomAD4 genome 0.000394 AC: 60AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29AN XY: 74446
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 23, 2024 | Published functional studies demonstrate impaired non-homologous end joining (PMID: 25728776); 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; This variant is associated with the following publications: (PMID: 26822949, 25839420, 31980526, 34426522, 25728776, 35595529) - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.His9Thrfs*8) 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). This variant is present in population databases (rs757928483, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with short stature, microcephaly, and endocrine dysfunction (PMID: 25728776, 25839420). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 208515). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 28, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | XRCC4: PVS1, PM2 - |
Short stature, microcephaly, and endocrine dysfunction Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 27, 2020 | The p.His9ThrfsX8 variant in XRCC4 has been reported in the compound heterozygous state in 4 individuals with clinical features of primordial microcephalic dwarfism and segregated with disease in 1 affected relative (Murray 2015 PMID: 25728776, Rosin 2015 PMID: 25839420). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 208515) and been identified in 0.083% (107/128924) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 9 and leads to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the XRCC4 gene has been strongly associated with short stature, microcephaly, and endocrine dysfunction. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive short stature, microcephaly, and endocrine dysfunction. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PP1. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | - | XRCC4 c.25delC, [p.H9fs] is a frameshift variant predicted to result in premature truncation or absence of XRCC4 protein. This variant has previously been reported in microcephaly and prenatal-onset global growth failure and is considered likely pathogenic (PMID:25728776; 25839420). - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 22, 2022 | Variant summary: XRCC4 c.25delC (p.His9ThrfsX8) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position are classified as pathogenic in ClinVar. The variant allele was found at a frequency of 0.00039 in 251062 control chromosomes. c.25delC has been reported in the literature in individuals affected with Microcephaly, primordial dwarfism, and unilateral renal agenesis (Murray_2015, Rosin_2015), and these individuals were reported as compound heterozygous, carrying other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
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