rs950490534

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_017802.4(DNAAF5):ā€‹c.2346C>Gā€‹(p.Tyr782*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,614,140 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 Pathogenic (ā˜…). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000039 ( 0 hom. )

Consequence

DNAAF5
NM_017802.4 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.370
Variant links:
Genes affected
DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 7-780059-C-G is Pathogenic according to our data. Variant chr7-780059-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 454860.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF5NM_017802.4 linkuse as main transcriptc.2346C>G p.Tyr782* stop_gained 12/13 ENST00000297440.11 NP_060272.3 Q86Y56-1B3KPE2
DNAAF5XM_024446813.2 linkuse as main transcriptc.2239+4897C>G intron_variant XP_024302581.1
DNAAF5NR_075098.2 linkuse as main transcriptn.2306C>G non_coding_transcript_exon_variant 12/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF5ENST00000297440.11 linkuse as main transcriptc.2346C>G p.Tyr782* stop_gained 12/131 NM_017802.4 ENSP00000297440.6 Q86Y56-1
DNAAF5ENST00000403952.3 linkuse as main transcriptc.621C>G p.Tyr207* stop_gained 5/61 ENSP00000384884.3 E9PGY2
DNAAF5ENST00000440747.5 linkuse as main transcriptc.1749C>G p.Tyr583* stop_gained 12/132 ENSP00000403165.1 H0Y650
DNAAF5ENST00000461576.1 linkuse as main transcriptn.156C>G non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152274
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251412
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135882
show subpopulations
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:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000390
AC:
57
AN:
1461866
Hom.:
0
Cov.:
31
AF XY:
0.0000371
AC XY:
27
AN XY:
727230
show subpopulations
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:
0.0000477
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152274
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
EpiCase
AF:
0.0000545
EpiControl
AF:
0.0000593

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 11, 2020This sequence change creates a premature translational stop signal (p.Tyr782*) in the DNAAF5 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DNAAF5-related disease. ClinVar contains an entry for this variant (Variation ID: 454860). Loss-of-function variants in DNAAF5 are known to be pathogenic (PMID: 24307375, 25232951). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.61
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
34
DANN
Uncertain
0.98
Eigen
Benign
-0.082
Eigen_PC
Benign
-0.44
FATHMM_MKL
Benign
0.031
N
Vest4
0.15
ClinPred
0.87
D
GERP RS
0.59
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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.

Other links and lift over

dbSNP: rs950490534; hg19: chr7-819696; COSMIC: COSV52416415; COSMIC: COSV52416415; API