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5-83104942-TC-T

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

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.869
Variant links:
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
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
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
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
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
XRCC4NM_003401.5 linkuse as main transcriptc.25del p.His9ThrfsTer8 frameshift_variant 2/8 ENST00000396027.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XRCC4ENST00000396027.9 linkuse as main transcriptc.25del p.His9ThrfsTer8 frameshift_variant 2/85 NM_003401.5 A1Q13426-2

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000394
AC:
60
AN:
152138
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000765
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000394
AC:
99
AN:
251062
Hom.:
0
AF XY:
0.000405
AC XY:
55
AN XY:
135710
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000262
Gnomad FIN exome
AF:
0.000416
Gnomad NFE exome
AF:
0.000696
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000420
AC:
613
AN:
1461012
Hom.:
0
Cov.:
30
AF XY:
0.000407
AC XY:
296
AN XY:
726850
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000220
Gnomad4 FIN exome
AF:
0.000318
Gnomad4 NFE exome
AF:
0.000497
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000394
AC:
60
AN:
152256
Hom.:
0
Cov.:
32
AF XY:
0.000390
AC XY:
29
AN XY:
74446
show subpopulations
Gnomad4 AFR
AF:
0.0000722
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.000765
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000299
Hom.:
0
Bravo
AF:
0.000264
Asia WGS
AF:
0.000289
AC:
1
AN:
3474
EpiCase
AF:
0.000709
EpiControl
AF:
0.000889

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenDec 01, 2023XRCC4: PVS1, PM2 -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 28, 2016- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 12, 2024This 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. -
Short stature, microcephaly, and endocrine dysfunction Pathogenic:5
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 27, 2020The 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 providedliterature onlyOMIMJul 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 22, 2022Variant 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. -
Likely pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJun 30, 2021- -
Likely pathogenic, criteria provided, single submitterresearchUNC 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). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs869320677; hg19: chr5-82400761; API