chr5-83105046-T-C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_003401.5(XRCC4):c.127T>C(p.Trp43Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000753 in 1,460,594 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 (★★).
Frequency
Consequence
NM_003401.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
XRCC4 | NM_003401.5 | c.127T>C | p.Trp43Arg | missense_variant | Exon 2 of 8 | ENST00000396027.9 | NP_003392.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 250224Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135256
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460594Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 726576
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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The W43R pathogenic variant in the XRCC4 gene has been reported previously in the homozygous state in at least two individuals with microcephalic primordial dwarfism (Shaheen et al., 2014; Murray et al., 2015). Functional studies demonstrate that this variant impairs XRCC4 function and results in greatly reduced protein levels as compared to wild type (Murray et al., 2015; Guo et al., 2015). The W43R variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret W43R as a pathogenic variant. -
Short stature, microcephaly, and endocrine dysfunction Pathogenic:2
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Ateleiotic dwarfism Pathogenic:1
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XRCC4-related disorder Pathogenic:1
The XRCC4 c.127T>C variant is predicted to result in the amino acid substitution p.Trp43Arg. This variant has been reported in the homozygous state in individuals with short stature and microcephaly (Shaheen et al. 2014. PubMed ID: 24389050; Shaheen et al. 2018. PubMed ID: 30214071; Asa et al. 2021. PubMed ID: 33842963). Functional studies showed that this variant impacts protein functions (Murray et al. 2015. PubMed ID: 25728776; Asa et al. 2021. PubMed ID: 33842963). This variant is reported in 0.013% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at