chr21-44339161-C-CTGCACGCTGTGCAGCT

Position:

chr21-44339161-C-CTGCACGCTGTGCAGCT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The ENST00000339818.9(CFAP410):c.33_34insAGCTGCACAGCGTGCA(p.Ala12SerfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00008 in 1,474,772 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R11R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

CFAP410
ENST00000339818.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.0680

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 43 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 21-44339161-C-CTGCACGCTGTGCAGCT is Pathogenic according to our data. Variant chr21-44339161-C-CTGCACGCTGTGCAGCT is described in ClinVar as [Pathogenic]. Clinvar id is 438159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP410	NM_004928.3 linkuse as main transcript	c.33_34insAGCTGCACAGCGTGCA	p.Ala12SerfsTer60	frameshift_variant	1/7	ENST00000339818.9	NP_004919.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP410	ENST00000339818.9 linkuse as main transcript	c.33_34insAGCTGCACAGCGTGCA	p.Ala12SerfsTer60	frameshift_variant	1/7	1	NM_004928.3	ENSP00000344566	P4	O43822-1
CFAP410	ENST00000325223.7 linkuse as main transcript	c.33_34insAGCTGCACAGCGTGCA	p.Ala12SerfsTer60	frameshift_variant	1/7	1		ENSP00000317302	A1	O43822-3
CFAP410	ENST00000397956.7 linkuse as main transcript	c.33_34insAGCTGCACAGCGTGCA	p.Ala12SerfsTer60	frameshift_variant	1/7	1		ENSP00000381047		O43822-4

Frequencies

GnomAD3 genomes

AF:

0.0000790

AC:

AN:

151840

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000436

AC:

AN:

91818

Hom.:

AF XY:

0.0000388

AC XY:

AN XY:

51562

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000137

Gnomad NFE exome

AF:

0.0000633

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000801

AC:

106

AN:

1322932

Hom.:

Cov.:

AF XY:

0.0000736

AC XY:

AN XY:

652506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000171

Gnomad4 NFE exome

AF:

0.0000931

Gnomad4 OTH exome

AF:

0.0000184

GnomAD4 genome

AF:

0.0000790

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74176

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000216

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 20, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 438159). This premature translational stop signal has been observed in individuals with retinal dystrophy (PMID: 28041643). This variant is present in population databases (rs748531024, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Ala12Serfs*60) in the CFAP410 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFAP410 are known to be pathogenic (PMID: 23105016, 26167768). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed with a second pathogenic variant in a patient with retinitis pigmentosa in published literature (Carss et al., 2017), although the phase of these two variants was not confirmed; This variant is associated with the following publications: (PMID: 32581362, 28041643) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	CFAP410: PVS1, PM2 -

Retinal dystrophy

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2020	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Retinitis pigmentosa

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -

CFAP410-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2024

The CFAP410 c.33_34insAGCTGCACAGCGTGCA variant is predicted to result in a frameshift and premature protein termination (p.Ala12Serfs*60). This variant has been reported in individuals with retinitis pigmentosa (see for examples: Carss et al. 2016. PubMed ID: 28041643; Areblom et al. 2023. PubMed ID: 37510321; Table S1, Lin et al. 2024. PubMed ID: 38219857). This variant is reported in 0.017% of alleles in individuals of European (Finnish) descent in gnomAD. Frameshift variants in CFAP410 are an established mechanism of disease. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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