rs754773453

chr11-102066649-A-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_032930.3(CFAP300):c.433A>T(p.Arg145Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000691 in 1,448,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: CFAP300 NM_032930.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9392
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.42

Genes affected

CFAP300 (HGNC:28188): (cilia and flagella associated protein 300) Predicted to be located in cytoplasm and motile cilium. Implicated in primary ciliary dyskinesia 38. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-102066649-A-T is Pathogenic according to our data. Variant chr11-102066649-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 549861.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-102066649-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFAP300	NM_032930.3	c.433A>T	p.Arg145Ter	stop_gained, splice_region_variant	4/7	ENST00000434758.7
CFAP300	NM_001363505.2	c.433A>T	p.Arg145Ter	stop_gained, splice_region_variant	4/6
CFAP300	XM_005271713.5	c.433A>T	p.Arg145Ter	stop_gained, splice_region_variant	4/6
CFAP300	NM_001195005.2	c.268+7694A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFAP300	ENST00000434758.7	c.433A>T	p.Arg145Ter	stop_gained, splice_region_variant	4/7	2	NM_032930.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000210 AC: 5 AN: 238508 Hom.: 0 AF XY: 0.0000311 AC XY: 4 AN XY: 128788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000362

Gnomad OTH exome AF: 0.000170

GnomAD4 exome AF: 0.00000691 AC: 10 AN: 1448210 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 719708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000902

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

This sequence change creates a premature translational stop signal (p.Arg145*) in the C11orf70 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in C11orf70 are known to be pathogenic (PMID: 29727692, 29727693). This variant is present in population databases (rs754773453, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 29727693). ClinVar contains an entry for this variant (Variation ID: 549861). For these reasons, this variant has been classified as Pathogenic. -

Ciliary dyskinesia, primary, 38 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Uncertain	0.97	D
MutationTaster	Benign	1.0	A;A;D
Vest4		0.27
ClinPred		1.0	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.010		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: rs754773453; hg19: chr11-101937380;