rs754773453

Variant names:

• chr11-102066649-A-T
• rs754773453
• NM_032930.3:c.433A>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_032930.3(CFAP300):​c.433A>T​(p.Arg145*) 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 benign outcome for this variant. 3/3 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
• Publications: 1 publications found

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]

CFAP300 Gene-Disease associations (from GenCC):

• ciliary dyskinesia, primary, 38

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-102066649-A-T is Pathogenic according to our data. Variant chr11-102066649-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 549861.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032930.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP300	NM_032930.3	MANE Select	c.433A>T	p.Arg145*	stop_gained splice_region	Exon 4 of 7	NP_116319.2	Q9BRQ4-1
	CFAP300	NM_001441265.1		c.433A>T	p.Arg145*	stop_gained splice_region	Exon 4 of 6	NP_001428194.1
	CFAP300	NM_001363505.2		c.433A>T	p.Arg145*	stop_gained splice_region	Exon 4 of 6	NP_001350434.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFAP300	ENST00000434758.7	TSL:2 MANE Select	c.433A>T	p.Arg145*	stop_gained splice_region	Exon 4 of 7	ENSP00000414390.2	Q9BRQ4-1
	CFAP300	ENST00000534360.1	TSL:1	c.268+7694A>T		intron	N/A	ENSP00000435482.1	Q9BRQ4-3
	CFAP300	ENST00000530659.1	TSL:1	n.670A>T		splice_region non_coding_transcript_exon	Exon 3 of 6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000210 AC: 5 AN: 238508 AF XY: 0.0000311

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32794

American (AMR) AF: 0.00 AC: 0 AN: 40960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25782

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 81906

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5380

European-Non Finnish (NFE) AF: 0.00000902 AC: 10 AN: 1109066

Other (OTH) AF: 0.00 AC: 0 AN: 59996

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ciliary dyskinesia, primary, 38 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.4
Vest4		0.27
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.015	Neutral
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs754773453; hg19: chr11-101937380;