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):c.218G>C(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 (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

CFAP410
NM_004928.3 missense

Scores

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]

CFAP410 links:

ENSG00000184441 (HGNC:):

ENSG00000184441 links:

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
CFAP410	NM_004928.3 link	c.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
CFAP410	ENST00000339818.9 link	c.218G>C	p.Arg73Pro	missense_variant	4/7	1	NM_004928.3	ENSP00000344566.4		O43822-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152248

Hom.:

Cov.:

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:

AN:

245166

Hom.:

AF XY:

0.000368

AC XY:

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.:

Cov.:

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:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

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.:

Bravo

AF:

0.000253

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

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 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.032

T;.;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.13

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.1

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over