rs140451304

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PM1PM2PP5_Very_StrongBP4BS1_Supporting

The NM_004928.3(CFAP410):ā€‹c.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

Scores

1
3
13

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: -0.0310
Variant links:
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]

Genome browser will be placed here

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
CFAP410NM_004928.3 linkc.218G>C p.Arg73Pro missense_variant 4/7 ENST00000339818.9 NP_004919.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFAP410ENST00000339818.9 linkc.218G>C p.Arg73Pro missense_variant 4/71 NM_004928.3 ENSP00000344566.4 O43822-1

Frequencies

GnomAD3 genomes
AF:
0.000361
AC:
55
AN:
152248
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000706
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000306
AC:
75
AN:
245166
Hom.:
0
AF XY:
0.000368
AC XY:
49
AN XY:
133252
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000942
Gnomad NFE exome
AF:
0.000633
Gnomad OTH exome
AF:
0.000500
GnomAD4 exome
AF:
0.000517
AC:
755
AN:
1460390
Hom.:
0
Cov.:
31
AF XY:
0.000535
AC XY:
389
AN XY:
726460
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000574
Gnomad4 NFE exome
AF:
0.000651
Gnomad4 OTH exome
AF:
0.000431
GnomAD4 genome
AF:
0.000361
AC:
55
AN:
152248
Hom.:
0
Cov.:
34
AF XY:
0.000323
AC XY:
24
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000706
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000305
Hom.:
0
Bravo
AF:
0.000253
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000313
AC:
38
EpiCase
AF:
0.000600
EpiControl
AF:
0.000237

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 submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaApr 28, 2019This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 17, 2022Published 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024CFAP410: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4 -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024This 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 submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteOct 09, 2024Based 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 submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The 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 submitterclinical testingBlueprint GeneticsJun 26, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2023- -
Retinitis pigmentosa Pathogenic:2
Likely pathogenic, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Likely pathogenic, criteria provided, single submittercurationBroad Center for Mendelian Genomics, Broad Institute of MIT and HarvardApr 01, 2021The 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 providedclinical testingPreventionGenetics, part of Exact SciencesSep 10, 2024The 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 providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Axial spondylometaphyseal dysplasia Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMAug 01, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.032
T;.;.
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.13
N
LIST_S2
Uncertain
0.94
D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.1
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Benign
0.094
Sift
Benign
0.24
T;T;T
Sift4G
Benign
0.29
T;T;T
Polyphen
0.94
P;.;.
Vest4
0.64
MVP
0.20
MPC
0.46
ClinPred
0.11
T
GERP RS
2.0
Varity_R
0.41
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs140451304; hg19: chr21-45753071; COSMIC: COSV100297217; COSMIC: COSV100297217; API