8-95245287-G-A

Position:

• chr8-95245287-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_177965.4(CFAP418):​c.*2330C>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 0.0166 in 152,076 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (44 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: CFAP418 NM_177965.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.939

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-95245287-G-A is Benign according to our data. Variant chr8-95245287-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 363983.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0166 (2531/152076) while in subpopulation NFE AF= 0.0188 (1281/67990). AF 95% confidence interval is 0.018. There are 44 homozygotes in gnomad4. There are 1410 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 44 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP418	NM_177965.4	c.*2330C>T		3_prime_UTR_variant	6/6	ENST00000286688.6
CFAP418	NM_001363260.1	c.*2330C>T		3_prime_UTR_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP418	ENST00000286688.6	c.*2330C>T		3_prime_UTR_variant	6/6	1	NM_177965.4	P1
CFAP418-AS1	ENST00000517655.1	n.521+39975G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2519 AN: 151958 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.00324

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00500

Gnomad SAS AF: 0.0170

Gnomad FIN AF: 0.0637

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0144

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.0166 AC: 2531 AN: 152076 Hom.: 44 Cov.: 32 AF XY: 0.0190 AC XY: 1410 AN XY: 74334

Gnomad4 AFR AF: 0.00328

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.0637

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0194

Alfa AF: 0.0191 Hom.: 2

Bravo AF: 0.0117

Asia WGS AF: 0.0230 AC: 78 AN: 3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Cone-rod dystrophy 16 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	6.4
DANN	Benign	0.67

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: rs150859301; hg19: chr8-96257515;