rs143740376

Positions:

chr21-32609853-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_021254.4(CFAP298):c.292C>T(p.Arg98*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000713 in 1,613,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

CFAP298
NM_021254.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.88

Variant links:

Genes affected

CFAP298 (HGNC:1301): (cilia and flagella associated protein 298) This gene encodes a protein that plays a critical role in dynein arm assembly and motile cilia function. Mutations in this gene result in primary ciliary dyskinesia. Naturally occuring readthrough transcription occurs from this locus to the downstream t-complex 10 like (TCP10L) gene. [provided by RefSeq, Apr 2017]

CFAP298 links:

CFAP298-TCP10L (HGNC:54636): (CFAP298-TCP10L readthrough) This locus represents naturally occurring readthrough transcription between the neighboring chromosome 21 open reading frame 59 (C21orf59) and TCP10L (t-complex 10 like) genes on chromosome 21. Readthrough transcripts may encode a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

CFAP298-TCP10L links:

CFAP298-TCP10L (HGNC:):

CFAP298-TCP10L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 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 21-32609853-G-A is Pathogenic according to our data. Variant chr21-32609853-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 88689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFAP298	NM_021254.4 linkuse as main transcript	c.292C>T	p.Arg98*	stop_gained	2/7	ENST00000290155.8	NP_067077.1	P57076

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFAP298	ENST00000290155.8 linkuse as main transcript	c.292C>T	p.Arg98*	stop_gained	2/7	1	NM_021254.4	ENSP00000290155.3		P57076
CFAP298-TCP10L	ENST00000673807.1 linkuse as main transcript	c.292C>T	p.Arg98*	stop_gained	2/8			ENSP00000501088.1		A0A669KAY3

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151850

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000394

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251182

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135754

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461538

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727068

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000801

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.0000856

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 26

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 03, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 88689). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24094744). This variant is present in population databases (rs143740376, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg98*) in the CFAP298 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFAP298 are known to be pathogenic (PMID: 24094744). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.96

Vest4

0.43, 0.41, 0.41

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over