Variant rs764066045 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_178452.6(DNAAF1):c.1645-2A>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000889 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

DNAAF1
NM_178452.6 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.024334252 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-84174667-A-C is Pathogenic according to our data. Variant chr16-84174667-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 455001.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.1645-2A>C		splice_acceptor_variant		ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.1645-2A>C	splice_acceptor_variant		1	NM_178452.6	ENSP00000367815	P1	Q8NEP3-1
DNAAF1	ENST00000570298.5 linkuse as main transcript	n.4090A>C	non_coding_transcript_exon_variant	9/11	2
DNAAF1	ENST00000563093.5 linkuse as main transcript	c.*200-2A>C	splice_acceptor_variant, NMD_transcript_variant		2		ENSP00000457373		Q8NEP3-3
DNAAF1	ENST00000563818.5 linkuse as main transcript	n.1322-2A>C	splice_acceptor_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000477

AC:

AN:

251466

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000347

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000291

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change affects an acceptor splice site in intron 9 of the DNAAF1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAAF1 are known to be pathogenic (PMID: 19944400, 19944405). This variant is present in population databases (rs764066045, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 455001). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.91

MutationTaster

Benign

1.0

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.81

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.81

Position offset: 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