1-196977712-T-TG
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_030787.4(CFHR5):c.53dup(p.Glu19ArgfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CFHR5
NM_030787.4 frameshift
NM_030787.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0610
Genes affected
CFHR5 (HGNC:24668): (complement factor H related 5) This gene is a member of a small complement factor H (CFH) gene cluster on chromosome 1. Each member of this gene family contains multiple short consensus repeats (SCRs) typical of regulators of complement activation. The protein encoded by this gene has nine SCRs with the first two repeats having heparin binding properties, a region within repeats 5-7 having heparin binding and C reactive protein binding properties, and the C-terminal repeats being similar to a complement component 3 b (C3b) binding domain. This protein co-localizes with C3, binds C3b in a dose-dependent manner, and is recruited to tissues damaged by C-reactive protein. Allelic variations in this gene have been associated, but not causally linked, with two different forms of kidney disease: membranoproliferative glomerulonephritis type II (MPGNII) and hemolytic uraemic syndrome (HUS). [provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFHR5 | NM_030787.4 | c.53dup | p.Glu19ArgfsTer6 | frameshift_variant | 1/10 | ENST00000256785.5 | |
CFHR5 | XM_011510020.3 | c.67+2603dup | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFHR5 | ENST00000256785.5 | c.53dup | p.Glu19ArgfsTer6 | frameshift_variant | 1/10 | 1 | NM_030787.4 | P1 | |
CFHR5 | ENST00000699466.1 | c.-198+2603dup | intron_variant | ||||||
CFHR5 | ENST00000699468.1 | c.-25+37dup | intron_variant | ||||||
CFHR5 | ENST00000699467.1 | n.127+2129dup | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251426Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460048Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726480
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GnomAD4 genome Cov.: 32
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32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
CFHR5 deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 04, 2020 | The inherited heterozygous c.53dup (p.Glu19ArgfsTer6) frameshift variant identified in this individual is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is absent from gnomAD database indicating it is an extremely rare allele in the general population. This frameshift variant has been reported in a patient with atypical hemolytic uremic syndrome who was also homozygous for CFHR1-3 deletion [PMID: 28056875]. Twelve out of thirteen predicted loss-of-function variants (frameshift, stop-gained-splice site) reported in ClinVar database are not classified as pathogenic/likely pathogenic. Loss-of-Function Intolerance score (pLI) for CFHR5gene is zero (gnomADv2). Due to the lack of compelling evidence in favor of Loss-of-function as the mechanism of disease for CFHR5 gene, the inherited heterozygous frameshift variant in the CFHR5 gene is assessed as a variant of uncertain significance. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at