Variant rs1060505042 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_177965.4(CFAP418):c.244-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CFAP418
NM_177965.4 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 4.72

Variant links:

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]

CFAP418 links:

CFAP418-AS1 (HGNC:50444): (CFAP418 antisense RNA 1)

CFAP418-AS1 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 6.5, offset of 22, new splice context is: attaaaatctaaatcttcAGgta. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-95260534-T-G is Pathogenic according to our data. Variant chr8-95260534-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 417787.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-95260534-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP418	NM_177965.4 linkuse as main transcript	c.244-2A>C		splice_acceptor_variant		ENST00000286688.6	NP_808880.1
CFAP418	NM_001363260.1 linkuse as main transcript	c.244-2A>C		splice_acceptor_variant			NP_001350189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP418	ENST00000286688.6 linkuse as main transcript	c.244-2A>C		splice_acceptor_variant		1	NM_177965.4	ENSP00000286688	P1
CFAP418-AS1	ENST00000517655.1 linkuse as main transcript	n.521+55222T>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CFAP418-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 14, 2024

The CFAP418 c.244-2A>C variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant segregated with disease in the homozygous state in three siblings with retinitis pigmentosa and was heterozygous in two unaffected siblings from a single consanguineous family. A minigene splicing assay revealed this variant activates a cryptic splice acceptor site that results in a 22 bp deletion, frameshift and premature termination (Ravesh et al. 2015. PubMed ID: 25802487). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice acceptor site in CFAP418 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa 64

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.65

Position offset: -24

DS_AL_spliceai

0.99

Position offset: -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