rs748014296
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_177965.4(CFAP418):c.555G>A(p.Trp185Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,850 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: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CFAP418
NM_177965.4 stop_gained
NM_177965.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.24
Genes affected
CFAP418 (HGNC:27232): (cilia and flagella associated protein 418) This gene encodes a ubiquitously expressed protein of unknown function. It has high levels of mRNA expression in the brain, heart, and retina and the protein co-localizes with polyglutamylated tubulin at the base of the primary cilium in human retinal pigment epithelial cells. Mutations in this gene have been associated with autosomal recessive cone-rod dystrophy (arCRD) and retinitis pigmentosa (arRP). [provided by RefSeq, Mar 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.111 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-95247686-C-T is Pathogenic according to our data. Variant chr8-95247686-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-95247686-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFAP418 | NM_177965.4 | c.555G>A | p.Trp185Ter | stop_gained | 6/6 | ENST00000286688.6 | |
CFAP418 | NM_001363260.1 | c.459G>A | p.Trp153Ter | stop_gained | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFAP418 | ENST00000286688.6 | c.555G>A | p.Trp185Ter | stop_gained | 6/6 | 1 | NM_177965.4 | P1 | |
CFAP418-AS1 | ENST00000517655.1 | n.521+42374C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251368Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135858
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727238
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2023 | Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 23 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25802487, 29843741, 31980526) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the C8orf37 protein in which other variant(s) (p.Trp202*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 417788). This premature translational stop signal has been observed in individual(s) with clinical features of inherited retinal dystrophy (PMID: 25802487, 29843741). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs748014296, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Trp185*) in the C8orf37 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the C8orf37 protein. - |
Retinitis pigmentosa 64 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 28, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at