rs114601492

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001256715.2(DNAAF3):c.1405G>A(p.Val469Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,078 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0081 ( 19 hom., cov: 33)

Exomes 𝑓: 0.00078 ( 15 hom. )

Consequence

DNAAF3
NM_001256715.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.11

Publications

1 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:

ENSG00000267110 (HGNC:):

ENSG00000267110 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002953142).

BP6

Variant 19-55159283-C-T is Benign according to our data. Variant chr19-55159283-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 369295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00807 (1230/152324) while in subpopulation AFR AF = 0.028 (1165/41564). AF 95% confidence interval is 0.0267. There are 19 homozygotes in GnomAd4. There are 586 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF3	NM_001256715.2 link	c.1405G>A	p.Val469Met	missense_variant	Exon 12 of 12	ENST00000524407.7	NP_001243644.1	Q8N9W5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7 link	c.1405G>A	p.Val469Met	missense_variant	Exon 12 of 12	1	NM_001256715.2	ENSP00000432046.3		Q8N9W5-1
ENSG00000267110	ENST00000587871.1 link	n.388G>A		non_coding_transcript_exon_variant	Exon 4 of 9	5		ENSP00000473050.1		M0R381

Frequencies

GnomAD3 genomes

AF:

0.00807

AC:

1228

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

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:

0.00623

GnomAD2 exomes

AF:

0.00212

AC:

529

AN:

249320

AF XY:

0.00166

show subpopulations

Gnomad AFR exome

AF:

0.0303

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.000991

GnomAD4 exome

AF:

0.000779

AC:

1138

AN:

1461754

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

474

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.0284

AC:

951

AN:

33480

American (AMR)

AF:

0.00152

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1112006

Other (OTH)

AF:

0.00152

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00807

AC:

1230

AN:

152324

Hom.:

Cov.:

AF XY:

0.00787

AC XY:

586

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0280

AC:

1165

AN:

41564

American (AMR)

AF:

0.00327

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00617

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

141

211

282

352

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00337

Hom.:

Bravo

AF:

0.00905

ESP6500AA

AF:

0.0250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00258

AC:

312

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 24, 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 provided

Benign:2

Jul 26, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

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

- -

Primary ciliary dyskinesia 2

Benign:1

Sep 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0039

.;T;.;.

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.61

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.90

.;L;.;.

PhyloP100

-1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.51

N;.;.;N

REVEL

Benign

0.070

Sift

Benign

0.060

T;.;.;D

Sift4G

Uncertain

0.054

T;T;T;T

Polyphen

0.96

.;D;.;.

Vest4

0.12

MVP

0.13

MPC

0.67

ClinPred

0.027

GERP RS

-0.29

Varity_R

0.019

gMVP

0.27

Mutation Taster

=100/0

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over