1-196994128-C-CA
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_030787.4(CFHR5):c.486dupA(p.Glu163ArgfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00359 in 1,612,922 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_030787.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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CFHR5 | ENST00000256785.5 | c.486dupA | p.Glu163ArgfsTer35 | frameshift_variant | Exon 4 of 10 | 1 | NM_030787.4 | ENSP00000256785.4 | ||
CFHR5 | ENST00000699466.1 | c.231dupA | p.Glu78ArgfsTer35 | frameshift_variant | Exon 4 of 10 | ENSP00000514393.1 | ||||
CFHR5 | ENST00000699468.1 | c.-24-1979dupA | intron_variant | Intron 1 of 5 | ENSP00000514394.1 | |||||
CFHR5 | ENST00000699467.1 | n.555dupA | non_coding_transcript_exon_variant | Exon 4 of 10 |
Frequencies
GnomAD3 genomes AF: 0.00216 AC: 328AN: 151658Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00203 AC: 510AN: 250704Hom.: 0 AF XY: 0.00200 AC XY: 271AN XY: 135512
GnomAD4 exome AF: 0.00374 AC: 5468AN: 1461146Hom.: 14 Cov.: 30 AF XY: 0.00366 AC XY: 2662AN XY: 726892
GnomAD4 genome AF: 0.00216 AC: 328AN: 151776Hom.: 2 Cov.: 32 AF XY: 0.00206 AC XY: 153AN XY: 74162
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
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Identified in individuals with renal disease, however, it has also been reported in clinically asymptomatic individuals (Monteferrante et al., 2007; Vernon et al., 2012; Figueres et al., 2014; Schapiro et al., 2019); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Observed in one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; Also known as c.485dupA and Asn1975Stop using alternate nomenclature; This variant is associated with the following publications: (PMID: 30295827, 31664448, 22503529, 25260719, 17000000, 31980526) -
CFHR5 deficiency Uncertain:2Benign:1
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not specified Uncertain:2
Variant summary: CFHR5 c.486dupA (p.Glu163ArgfsX35) 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, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant allele was found at a frequency of 0.002 in 251100 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in CFHR5 causing CFHR5 Deficiency phenotype. c.486dupA has been reported in the literature in individuals affected with CFHR5 Deficiency as well as in at least three healthy individuals (Monteferrante_2006, Vernon_2012, Figueres_2014, Benson_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32723786, 25260719, 31664448, 17000000, 28750028, 30295827, 22527104, 28054583, 22503529). ClinVar contains an entry for this variant (Variation ID: 402534). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Variant classified as Uncertain Significance - Favor Benign. The p.Glu163ArgfsX3 5 variant in CFHR5 (also reported as p.Glu163Arg and p.Asn197Stop) has been prev iously reported in at least two heterozygous individuals with CFHR5-deficiency a nd complement-mediated kidney diseases, as well as at least three asymptomatic i ndividuals (1 control and 2 family members of 1 of the heterozygotes; Monteferra nte 2007, Vernon 2012, and Figueres 2014). This variant has also been reported i n ClinVar (Variation ID#402534). It has been identified in 0.31% (395/126014) Eu ropean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstit ute.org; rs565457964). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 163 and leads to a premature termination codon 35 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, while the clinica l significance of the p.Glu163ArgfsX35 variant is uncertain, these data suggest that it is more likely to be benign. -
C3 glomerulonephritis Pathogenic:1
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Chronic kidney disease Uncertain:1
PVS1, BS1 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at