Genetic Variant DNAAF3:p.Ala222Ala (chr19-55161416-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001256715.2(DNAAF3):c.666T>C(p.Ala222Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 750,756 control chromosomes in the GnomAD database, including 25,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5891 hom., cov: 23)

Exomes 𝑓: 0.35 ( 19588 hom. )

Consequence

DNAAF3
NM_001256715.2 splice_region, synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.00300

Publications

10 publications found

Variant links:

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 links:

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

DNAAF3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BP6

Variant 19-55161416-A-G is Benign according to our data. Variant chr19-55161416-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 257694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.003 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001256715.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF3	NM_001256715.2	MANE Select	c.666T>C	p.Ala222Ala	splice_region synonymous	Exon 7 of 12	NP_001243644.1
DNAAF3	NM_001256714.1		c.870T>C	p.Ala290Ala	splice_region synonymous	Exon 7 of 12	NP_001243643.1
DNAAF3	NM_178837.4		c.807T>C	p.Ala269Ala	splice_region synonymous	Exon 7 of 12	NP_849159.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF3	ENST00000524407.7	TSL:1 MANE Select	c.666T>C	p.Ala222Ala	splice_region synonymous	Exon 7 of 12	ENSP00000432046.3
DNAAF3	ENST00000455045.5	TSL:1	c.504T>C	p.Ala168Ala	splice_region synonymous	Exon 7 of 12	ENSP00000394343.1
DNAAF3	ENST00000528412.5	TSL:1	n.*454T>C		splice_region non_coding_transcript_exon	Exon 7 of 12	ENSP00000433826.2

Frequencies

GnomAD3 genomes

AF:

0.270

AC:

34601

AN:

128230

Hom.:

5876

Cov.:

show subpopulations

Gnomad AFR

AF:

0.511

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.198

Gnomad ASJ

AF:

0.278

Gnomad EAS

AF:

0.117

Gnomad SAS

AF:

0.181

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.324

Gnomad NFE

AF:

0.167

Gnomad OTH

AF:

0.271

GnomAD2 exomes

AF:

0.184

AC:

33237

AN:

180944

AF XY:

0.181

show subpopulations

Gnomad AFR exome

AF:

0.514

Gnomad AMR exome

AF:

0.144

Gnomad ASJ exome

AF:

0.292

Gnomad EAS exome

AF:

0.0935

Gnomad FIN exome

AF:

0.105

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.219

GnomAD4 exome

AF:

0.349

AC:

217470

AN:

622406

Hom.:

19588

Cov.:

AF XY:

0.333

AC XY:

107367

AN XY:

322002

show subpopulations

African (AFR)

AF:

0.624

AC:

15375

AN:

24634

American (AMR)

AF:

0.189

AC:

4268

AN:

22556

Ashkenazi Jewish (ASJ)

AF:

0.413

AC:

5899

AN:

14298

East Asian (EAS)

AF:

0.164

AC:

2024

AN:

12350

South Asian (SAS)

AF:

0.187

AC:

11063

AN:

59116

European-Finnish (FIN)

AF:

0.165

AC:

5401

AN:

32658

Middle Eastern (MID)

AF:

0.426

AC:

1368

AN:

3214

European-Non Finnish (NFE)

AF:

0.379

AC:

161709

AN:

426254

Other (OTH)

AF:

0.379

AC:

10363

AN:

27326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

8612

17223

25835

34446

43058

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5970

11940

17910

23880

29850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.270

AC:

34661

AN:

128350

Hom.:

5891

Cov.:

AF XY:

0.265

AC XY:

16285

AN XY:

61544

show subpopulations

African (AFR)

AF:

0.511

AC:

18853

AN:

36860

American (AMR)

AF:

0.198

AC:

2419

AN:

12232

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

870

AN:

3126

East Asian (EAS)

AF:

0.116

AC:

391

AN:

3380

South Asian (SAS)

AF:

0.180

AC:

598

AN:

3316

European-Finnish (FIN)

AF:

0.131

AC:

959

AN:

7300

Middle Eastern (MID)

AF:

0.316

AC:

AN:

250

European-Non Finnish (NFE)

AF:

0.167

AC:

9875

AN:

59284

Other (OTH)

AF:

0.273

AC:

489

AN:

1794

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

1089

2177

3266

4354

5443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

316

632

948

1264

1580

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.202

Hom.:

2248

Bravo

AF:

0.259

Asia WGS

AF:

0.162

AC:

563

AN:

3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Primary ciliary dyskinesia 2

Benign:2

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dilated Cardiomyopathy, Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hypertrophic cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Familial restrictive cardiomyopathy

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

7.8

(source)

DANN

Benign

0.63

PhyloP100

-0.0030

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over