rs369869993
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_003824.4(FADD):āc.313T>Cā(p.Cys105Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000101 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Consequence
NM_003824.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251254Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135818
GnomAD4 exome AF: 0.000105 AC: 154AN: 1461814Hom.: 0 Cov.: 31 AF XY: 0.0000908 AC XY: 66AN XY: 727210
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74310
ClinVar
Submissions by phenotype
not provided Pathogenic:2
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FADD-related immunodeficiency Pathogenic:1Uncertain:1
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This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 105 of the FADD protein (p.Cys105Arg). This variant is present in population databases (rs369869993, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of FADD deficiency (PMID: 25326637, 32350755). ClinVar contains an entry for this variant (Variation ID: 242496). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Cys105 amino acid residue in FADD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21109225, 25794656). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at