rs922930539

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_004928.3(CFAP410):c.347C>T(p.Pro116Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,599,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

CFAP410
NM_004928.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.30

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain LRRCT (size 40) in uniprot entity CF410_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_004928.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.889

PP5

Variant 21-44333059-G-A is Pathogenic according to our data. Variant chr21-44333059-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-44333059-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-44333059-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP410	NM_004928.3 linkuse as main transcript	c.347C>T	p.Pro116Leu	missense_variant	4/7	ENST00000339818.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP410	ENST00000339818.9 linkuse as main transcript	c.347C>T	p.Pro116Leu	missense_variant	4/7	1	NM_004928.3	P4	O43822-1
	ENST00000448927.1 linkuse as main transcript	n.1704+122G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000599

AC:

AN:

233714

Hom.:

AF XY:

0.0000468

AC XY:

AN XY:

128114

show subpopulations

Gnomad AFR exome

AF:

0.0000703

Gnomad AMR exome

AF:

0.000208

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000229

Gnomad SAS exome

AF:

0.0000337

Gnomad FIN exome

AF:

0.0000508

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1447254

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

717420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000182

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000179

Gnomad4 SAS exome

AF:

0.0000469

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.0000163

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152392

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74524

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000283

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000414

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal dystrophy with or without macular staphyloma

Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	Henan Ocular Pharmacology and Therapeutics International Laboratory, Henan Eye Hospital	-	The P116L variant in CFAP410 has been reported in a family with axial spondylometaphyseal dysplasia (AXSMD) and located in the LRRCT domain. Another variant was Y107H. (Wang et al., 2016) -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Jan 17, 2024	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 116 of the CFAP410 protein (p.Pro116Leu). This variant is present in population databases (no rsID available, gnomAD 0.03%). This missense change has been observed in individuals with CFAP410-related conditions. (PMID: 26974433; Invitae). ClinVar contains an entry for this variant (Variation ID: 428581). 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 expected to disrupt CFAP410 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Axial spondylometaphyseal dysplasia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Uncertain

0.13

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.48

MutationTaster

Benign

1.0

D;D;D

PROVEAN

Pathogenic

-10

D;D;D

REVEL

Uncertain

0.44

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.90

MutPred

0.51

Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);Loss of disorder (P = 0.0514);

MVP

0.54

MPC

0.41

ClinPred

0.99

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.83

gMVP

0.63

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