rs1554718962
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001735.3(C5):c.4336delG(p.Val1446TrpfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,250 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
Consequence
NM_001735.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
C5 | NM_001735.3 | c.4336delG | p.Val1446TrpfsTer19 | frameshift_variant | Exon 35 of 41 | ENST00000223642.3 | NP_001726.2 | |
C5 | NM_001317163.2 | c.4354delG | p.Val1452TrpfsTer19 | frameshift_variant | Exon 35 of 41 | NP_001304092.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461250Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727016
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Complement component 5 deficiency Pathogenic:1
The p.Val1446TrpfsX19 (NM_001735.2 c.4336delG) variant in C5 has not been report ed in individuals with complement component 5 deficiency and was absent from lar ge population studies. This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 1446 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function o f the C5 gene is an established disease mechanism in complement component 5 defi ciency. In summary, although additional studies are required to fully establish its clinical significance, the p.Val1446TrpfsX19 variant is likely pathogenic fo r complement component 5 deficiency in an autosomal recessive manner based upon a predicted impact to the protein. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at