rs1085307121

Variant names:

• chr8-95269033-A-G
• rs1085307121
• NM_177965.4:c.155+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_177965.4(CFAP418):​c.155+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFAP418 NM_177965.4 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:3
• Conservation: PhyloP100: 3.28
• Publications: 2 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-95269033-A-G is Pathogenic according to our data. Variant chr8-95269033-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 417790.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177965.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP418	NM_177965.4	MANE Select	c.155+2T>C		splice_donor intron	N/A	NP_808880.1
	CFAP418	NM_001363260.1		c.155+2T>C		splice_donor intron	N/A	NP_001350189.1
	CFAP418-AS1	NR_038201.1		n.55+143A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP418	ENST00000286688.6	TSL:1 MANE Select	c.155+2T>C		splice_donor intron	N/A	ENSP00000286688.5
	CFAP418-AS1	ENST00000692571.1		n.202A>G		non_coding_transcript_exon	Exon 1 of 1
	CFAP418-AS1	ENST00000517437.2	TSL:3	n.78+143A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Cone-rod dystrophy 16 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	27
DANN	Benign	0.94
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.55	D
PhyloP100		3.3
GERP RS		3.1
PromoterAI		-0.056	Neutral
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: -29
DS_DL_spliceai		0.95		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1085307121; hg19: chr8-96281261;