8-95245125-G-A

Variant names:

• chr8-95245125-G-A
• rs529486839
• NM_177965.4:c.*2492C>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_177965.4(CFAP418):​c.*2492C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0013 (0 hom., cov: 32)
• Consequence: CFAP418 NM_177965.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0100

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

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00133 (202/152150) while in subpopulation NFE AF= 0.00182 (124/67988). AF 95% confidence interval is 0.00156. There are 0 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP418	NM_177965.4	c.*2492C>T		3_prime_UTR_variant	Exon 6 of 6	ENST00000286688.6	NP_808880.1
CFAP418	NM_001363260.1	c.*2492C>T		3_prime_UTR_variant	Exon 5 of 5		NP_001350189.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFAP418	ENST00000286688	c.*2492C>T		3_prime_UTR_variant	Exon 6 of 6	1	NM_177965.4	ENSP00000286688.5
CFAP418-AS1	ENST00000517655.1	n.521+39813G>A		intron_variant	Intron 2 of 2	4

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00182

Gnomad OTH AF: 0.000958

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74400

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00114

Gnomad4 NFE AF: 0.00182

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00132 Hom.: 0

Bravo AF: 0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Cone-rod dystrophy 16 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.0
DANN	Benign	0.84

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

Other links and lift over

dbSNP: rs529486839; hg19: chr8-96257353;