Genetic Variant DNAAF19:p.Tyr26* (chr17-44901076-C-A) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_213607.3(DNAAF19):c.78C>A(p.Tyr26*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y26Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

DNAAF19
NM_213607.3 stop_gained

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.113

Publications

0 publications found

Variant links:

Genes affected

DNAAF19 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

DNAAF19 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 17
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF19 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 20 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-44901076-C-A is Pathogenic according to our data. Variant chr17-44901076-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3582146.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF19	NM_213607.3	MANE Select	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	NP_998772.1	Q8IW40-1
DNAAF19	NM_001258395.2		c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	NP_001245324.1	Q8IW40-1
DNAAF19	NM_001258396.2		c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	NP_001245325.1	Q8IW40-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAAF19	ENST00000417826.3	TSL:1 MANE Select	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	ENSP00000391692.2	Q8IW40-1
DNAAF19	ENST00000410006.6	TSL:2	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	ENSP00000387252.1	Q8IW40-1
DNAAF19	ENST00000357776.6	TSL:2	c.78C>A	p.Tyr26*	stop_gained	Exon 2 of 4	ENSP00000350420.2	F8W6J8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 17 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.22

PhyloP100

0.11

Vest4

0.28

GERP RS

5.8

Mutation Taster

=19/181

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over