rs113374052

Variant names:

Variant summary

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

The NM_017802.4(DNAAF5):c.921C>A(p.Ser307Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0147 in 1,588,566 control chromosomes in the GnomAD database, including 229 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.013 ( 23 hom., cov: 34)

Exomes 𝑓: 0.015 ( 206 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0540

Publications

2 publications found

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]

DNAAF5 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 18
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAAF5 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=0.004960537).

BP6

Variant 7-741362-C-A is Benign according to our data. Variant chr7-741362-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241211.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0132 (2006/152338) while in subpopulation NFE AF = 0.0199 (1352/68030). AF 95% confidence interval is 0.019. There are 23 homozygotes in GnomAd4. There are 1001 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DNAAF5	NM_017802.4 link	c.921C>A	p.Ser307Arg	missense_variant	Exon 4 of 13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2 link	c.921C>A	p.Ser307Arg	missense_variant	Exon 4 of 12		XP_024302581.1
DNAAF5	NR_075098.2 link	n.881C>A		non_coding_transcript_exon_variant	Exon 4 of 13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
DNAAF5	ENST00000297440.11 link	c.921C>A	p.Ser307Arg	missense_variant	Exon 4 of 13	1	NM_017802.4	ENSP00000297440.6
DNAAF5	ENST00000440747.5 link	c.324C>A	p.Ser108Arg	missense_variant	Exon 4 of 13	2		ENSP00000403165.1
DNAAF5	ENST00000437419.5 link	c.237C>A	p.Ser79Arg	missense_variant	Exon 3 of 5	5		ENSP00000410788.1
DNAAF5	ENST00000438961.1 link	n.390C>A		non_coding_transcript_exon_variant	Exon 4 of 5	4

Frequencies

GnomAD3 genomes

AF:

0.0132

AC:

2006

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00929

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0335

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0115

GnomAD2 exomes

AF:

0.0118

AC:

2495

AN:

211058

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00168

Gnomad AMR exome

AF:

0.00441

Gnomad ASJ exome

AF:

0.00775

Gnomad EAS exome

AF:

0.0000630

Gnomad FIN exome

AF:

0.0282

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.00840

GnomAD4 exome

AF:

0.0148

AC:

21316

AN:

1436228

Hom.:

206

Cov.:

AF XY:

0.0146

AC XY:

10411

AN XY:

711832

show subpopulations

African (AFR)

AF:

0.00235

AC:

AN:

33204

American (AMR)

AF:

0.00448

AC:

181

AN:

40364

Ashkenazi Jewish (ASJ)

AF:

0.00771

AC:

197

AN:

25548

East Asian (EAS)

AF:

0.00

AC:

AN:

38882

South Asian (SAS)

AF:

0.00347

AC:

285

AN:

82074

European-Finnish (FIN)

AF:

0.0272

AC:

1406

AN:

51712

Middle Eastern (MID)

AF:

0.00338

AC:

AN:

4438

European-Non Finnish (NFE)

AF:

0.0168

AC:

18482

AN:

1100568

Other (OTH)

AF:

0.0113

AC:

672

AN:

59438

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

908

1816

2725

3633

4541

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.0132

AC:

2006

AN:

152338

Hom.:

Cov.:

AF XY:

0.0134

AC XY:

1001

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

41584

American (AMR)

AF:

0.00927

AC:

142

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00166

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0335

AC:

356

AN:

10622

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0199

AC:

1352

AN:

68030

Other (OTH)

AF:

0.0114

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

105

209

314

418

523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0170

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0148

AC:

ALSPAC

AF:

0.0174

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0159

AC:

137

ExAC

AF:

0.0107

AC:

1286

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 19, 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

Jun 16, 2020

GeneDx

Significance:Likely 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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 18

Benign:1

Oct 23, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.073

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0050

MetaSVM

Benign

-1.1

PhyloP100

0.054

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.0

REVEL

Benign

0.076

Sift

Benign

0.34

Sift4G

Benign

0.40

Polyphen

0.34

Vest4

0.14

MutPred

0.29

Gain of MoRF binding (P = 0.3096);

MPC

0.24

ClinPred

0.0043

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.036

gMVP

0.42

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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