rs28377509

chr19-55159457-T-Cchr19-55159457-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256715.2(DNAAF3):c.1239-8A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,612,414 control chromosomes in the GnomAD database, including 65,011 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (13146 hom., cov: 32)
  • Exomes 𝑓: 0.24 (51865 hom.)
• Consequence: DNAAF3 NM_001256715.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002193
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.43

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 19-55159457-T-C is Benign according to our data. Variant chr19-55159457-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55159457-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.649 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.1239-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000524407.7
DNAAF3-AS1	XR_007067344.1	n.137+12T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.1239-8A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.436T>C		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55473 AN: 151980 Hom.: 13106 Cov.: 32

Gnomad AFR AF: 0.655

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.215

Gnomad EAS AF: 0.440

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.227

Gnomad MID AF: 0.318

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.360

GnomAD3 exomes AF: 0.323 AC: 80248 AN: 248766 Hom.: 15869 AF XY: 0.314 AC XY: 42334 AN XY: 134946

Gnomad AFR exome AF: 0.670

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.213

Gnomad EAS exome AF: 0.422

Gnomad SAS exome AF: 0.422

Gnomad FIN exome AF: 0.226

Gnomad NFE exome AF: 0.208

Gnomad OTH exome AF: 0.313

GnomAD4 exome AF: 0.244 AC: 356674 AN: 1460316 Hom.: 51865 Cov.: 35 AF XY: 0.247 AC XY: 179529 AN XY: 726174

Gnomad4 AFR exome AF: 0.673

Gnomad4 AMR exome AF: 0.490

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.421

Gnomad4 SAS exome AF: 0.414

Gnomad4 FIN exome AF: 0.232

Gnomad4 NFE exome AF: 0.201

Gnomad4 OTH exome AF: 0.281

GnomAD4 genome AF: 0.365 AC: 55581 AN: 152098 Hom.: 13146 Cov.: 32 AF XY: 0.367 AC XY: 27290 AN XY: 74352

Gnomad4 AFR AF: 0.655

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.215

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.440

Gnomad4 FIN AF: 0.227

Gnomad4 NFE AF: 0.201

Gnomad4 OTH AF: 0.366

Alfa AF: 0.264 Hom.: 3563

Bravo AF: 0.391

Asia WGS AF: 0.521 AC: 1808 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 05, 2018

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.53
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs28377509; hg19: chr19-55670825; COSMIC: COSV61275217; COSMIC: COSV61275217;