rs140451304
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1PM2PP5_Very_StrongBP4BS1_Supporting
The NM_004928.3(CFAP410):āc.218G>Cā(p.Arg73Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,612,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: š 0.00036 ( 0 hom., cov: 34)
Exomes š: 0.00052 ( 0 hom. )
Consequence
CFAP410
NM_004928.3 missense
NM_004928.3 missense
Scores
1
3
13
Clinical Significance
Conservation
PhyloP100: -0.0310
Genes affected
CFAP410 (HGNC:1260): (cilia and flagella associated protein 410) Four alternatively spliced transcript variants encoding four different isoforms have been found for this nuclear gene. All isoforms contain leucine-rich repeats. Three of these isoforms are mitochondrial proteins and one of them lacks the target peptide, so is not located in mitochondrion. This gene is down-regulated in Down syndrome (DS) brain, which may represent mitochondrial dysfunction in DS patients. [provided by RefSeq, Sep 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a repeat LRR 3 (size 21) in uniprot entity CF410_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_004928.3
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 21-44333188-C-G is Pathogenic according to our data. Variant chr21-44333188-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44333188-C-G is described in Lovd as [Pathogenic]. Variant chr21-44333188-C-G is described in Lovd as [Pathogenic]. Variant chr21-44333188-C-G is described in Lovd as [Likely_pathogenic]. Variant chr21-44333188-C-G is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.13023537). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000361 (55/152248) while in subpopulation NFE AF= 0.000706 (48/68034). AF 95% confidence interval is 0.000547. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFAP410 | NM_004928.3 | c.218G>C | p.Arg73Pro | missense_variant | 4/7 | ENST00000339818.9 | NP_004919.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000361 AC: 55AN: 152248Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000306 AC: 75AN: 245166Hom.: 0 AF XY: 0.000368 AC XY: 49AN XY: 133252
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GnomAD4 exome AF: 0.000517 AC: 755AN: 1460390Hom.: 0 Cov.: 31 AF XY: 0.000535 AC XY: 389AN XY: 726460
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GnomAD4 genome AF: 0.000361 AC: 55AN: 152248Hom.: 0 Cov.: 34 AF XY: 0.000323 AC XY: 24AN XY: 74380
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Apr 28, 2019 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2022 | Published functional studies demonstrate a damaging effect with loss of C21orf2 protein function (Wheway et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27596865, 26974433, 26167768, 28422394, 28041643, 29343210, 31980526, 28771251, 32036094, 32581362, 31431468) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2024 | CFAP410: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 73 of the CFAP410 protein (p.Arg73Pro). This variant is present in population databases (rs140451304, gnomAD 0.07%). This missense change has been observed in individuals with Jeune asphyxiating thoracic dystrophy, cone-rod dystrophy or retinitis pigmentosa (PMID: 26167768, 27596865). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428573). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFAP410 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFAP410 function (PMID: 26167768). For these reasons, this variant has been classified as Pathogenic. - |
Retinal dystrophy with or without macular staphyloma Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy with macular staphyloma (MIM#617547) and axial spondylometaphyseal dysplasia (MIM#602271). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 90 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and low conservation. (I) 0600 - Variant is located in the annotated leucine-rich repeat domain (PMID: 26974433). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The variants p.(Arg73Gly), p.(Arg73Cys), and p.(Arg73His) have each been reported as variants of uncertain significance by a clinical laboratory (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with axial spondylometaphyseal dysplaisa (PMID: 26974433) and Jeune asphyxiating thoracic dystrophy (PMIDs: 26167768, 28422394). In addition, it has been reported as pathogenic/likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely pathogenic, criteria provided, single submitter | research | Ocular Genomics Institute, Massachusetts Eye and Ear | Apr 08, 2021 | The C21orf2 c.218G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1. Based on this evidence we have classified this variant as Likely Pathogenic. - |
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg | Jan 01, 2023 | - - |
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Apr 01, 2021 | The p.Arg73Pro variant in C21orf2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1. Based on this evidence we have classified this variant as Likely pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. - |
CFAP410-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2024 | The CFAP410 c.218G>C variant is predicted to result in the amino acid substitution p.Arg73Pro. This variant has been reported as segregating with disease in both the homozygous and compound heterozygous states in kindreds with Jeune syndrome or cone-rod dystrophy (Table S8, Wheway et al. 2015. PubMed ID: 26167768). This variant has also been reported along with a second CFAP410 variant in large cohort studies of retinal disease (Table S2, Carss et al. 2017. PubMed ID: 28041643; Zhang et al. 2016. PubMed ID: 27596865; Table S1, Lin. 2024. PubMed ID: 38219857). Additionally, this variant has been reported in the homozygous state in two families with axial spondylometaphyseal dysplasia (Wang et al. 2016. PubMed ID: 26974433). Functional studies suggested that p.Arg73Pro is a hypomorphic variant (Wheway et al. 2015. PubMed ID: 26167768). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic for autosomal recessive CFAP410-related disorders. - |
Cone dystrophy Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | NIHR Bioresource Rare Diseases, University of Cambridge | Jan 01, 2015 | - - |
Axial spondylometaphyseal dysplasia Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
P;.;.
Vest4
MVP
MPC
0.46
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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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