18-50227413-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The NM_145020.5(CFAP53):c.1513C>A(p.Arg505Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R505C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: CFAP53 NM_145020.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.105

Genes affected

CFAP53 (HGNC:26530): (cilia and flagella associated protein 53) This gene belongs to the CFAP53 family. It was found to be differentially expressed by the ciliated cells of frog epidermis and in skin fibroblasts from human. Mutations in this gene are associated with visceral heterotaxy-6, which implicates this gene in determination of left-right asymmetric patterning. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000361 (55/152326) while in subpopulation NFE AF= 0.000603 (41/68028). AF 95% confidence interval is 0.000457. There are 0 homozygotes in gnomad4. There are 22 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/exons	MANE	UniProt
CFAP53	NM_145020.5	c.1513C>A	p.Arg505Ser	missense_variant	8/8	ENST00000398545.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP53	ENST00000398545.5	c.1513C>A	p.Arg505Ser	missense_variant	8/8	1	NM_145020.5	P1

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000309 AC: 77 AN: 249468 Hom.: 0 AF XY: 0.000296 AC XY: 40 AN XY: 135352

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000530

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000545 AC: 796 AN: 1461724 Hom.: 1 Cov.: 30 AF XY: 0.000518 AC XY: 377 AN XY: 727144

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000656

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22 AN XY: 74498

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00000583 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000364 AC: 44

EpiCase AF: 0.000709

EpiControl AF: 0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2023

The c.1513C>A (p.R505S) alteration is located in exon 8 (coding exon 8) of the CCDC11 gene. This alteration results from a C to A substitution at nucleotide position 1513, causing the arginine (R) at amino acid position 505 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Heterotaxy, visceral, 6, autosomal Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2022

This variant is present in population databases (rs192619553, gnomAD 0.06%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with CFAP53-related conditions. This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 505 of the CFAP53 protein (p.Arg505Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.068	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.81
MVP		0.29
MPC		0.40
ClinPred		0.43	T
GERP RS		-1.5
Varity_R		0.15
gMVP		0.21

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: rs192619553; hg19: chr18-47753783;