rs140451304

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73G) has been classified as Uncertain significance.

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:15

Conservation

PhyloP100: -0.0310

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

axial spondylometaphyseal dysplasia
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cone-rod dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CFAP410 links:

ENSG00000184441 (HGNC:):

ENSG00000184441 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PP5

Variant 21-44333188-C-G is Pathogenic according to our data. Variant chr21-44333188-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP410	NM_004928.3 link	c.218G>C	p.Arg73Pro	missense_variant	Exon 4 of 7	ENST00000339818.9	NP_004919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP410	ENST00000339818.9 link	c.218G>C	p.Arg73Pro	missense_variant	Exon 4 of 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

GnomAD2 exomes

AF:

0.000306

AC:

AN:

245166

AF XY:

0.000368

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 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

African (AFR)

AF:

0.0000299

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.00

AC:

AN:

86204

European-Finnish (FIN)

AF:

0.0000574

AC:

AN:

52252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000651

AC:

724

AN:

1111850

Other (OTH)

AF:

0.000431

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

130

174

217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000361

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41464

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000706

AC:

AN:

68034

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CFAP410: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4 -

Jan 17, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Apr 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP5. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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:3

Feb 05, 2025

SingHealth Duke-NUS Institute of Precision Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Homozygous allele count in gnomAD exomes and genomes are less than 0 (PM2). Experimental studies have shown that this missense change affects CFAP410 function PS3, PMID: 26167768). There is cosegregation with disease phenotypes in multiple families (PP1, PMID: 26167768) -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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. -

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Retinal dystrophy

Pathogenic:2

Jun 26, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Pathogenic:2

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

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

Sep 10, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Axial spondylometaphyseal dysplasia;C4479651:Retinal dystrophy with or without macular staphyloma

Pathogenic:1

Jul 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Cone dystrophy

Pathogenic:1

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Axial spondylometaphyseal dysplasia

Pathogenic:1

Aug 01, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

(source)

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

PhyloP100

-0.031

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

Mutation Taster

=24/76

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over