Genetic Variant DNAAF5:p.Ala24Ala (chr7-726792-G-A) – 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_017802.4(DNAAF5):c.72G>A(p.Ala24Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00764 in 1,289,962 control chromosomes in the GnomAD database, including 623 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 377 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 246 hom. )

Consequence

DNAAF5
NM_017802.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.103

Publications

1 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 links:

PRKAR1B (HGNC:9390): (protein kinase cAMP-dependent type I regulatory subunit beta) The protein encoded by this gene is a regulatory subunit of cyclic AMP-dependent protein kinase A (PKA), which is involved in the signaling pathway of the second messenger cAMP. Two regulatory and two catalytic subunits form the PKA holoenzyme, disbands after cAMP binding. The holoenzyme is involved in many cellular events, including ion transport, metabolism, and transcription. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2015]

PRKAR1B Gene-Disease associations (from GenCC):

Marbach-Schaaf neurodevelopmental syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
PRKAR1B-related neurodegenerative dementia with intermediate filaments
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PRKAR1B 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=-0.89).

BP6

Variant 7-726792-G-A is Benign according to our data. Variant chr7-726792-G-A is described in ClinVar as Benign. ClinVar VariationId is 260938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.103 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.129 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017802.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF5	NM_017802.4	MANE Select	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 13	NP_060272.3
PRKAR1B	NM_001164760.2	MANE Select	c.-23+418C>T		intron	N/A	NP_001158232.1
DNAAF5	NR_075098.2		n.94G>A		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.72G>A	p.Ala24Ala	synonymous	Exon 1 of 13	ENSP00000297440.6
PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+418C>T		intron	N/A	ENSP00000440449.1
PRKAR1B	ENST00000403562.5	TSL:1	c.-23+798C>T		intron	N/A	ENSP00000385349.1

Frequencies

GnomAD3 genomes

AF:

0.0379

AC:

5750

AN:

151896

Hom.:

376

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000559

Gnomad OTH

AF:

0.0335

GnomAD2 exomes

AF:

0.00582

AC:

AN:

4810

AF XY:

0.00536

show subpopulations

Gnomad AFR exome

AF:

0.158

Gnomad AMR exome

AF:

0.00862

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000927

Gnomad OTH exome

AF:

0.00595

GnomAD4 exome

AF:

0.00360

AC:

4094

AN:

1137956

Hom.:

246

Cov.:

AF XY:

0.00326

AC XY:

1782

AN XY:

546492

show subpopulations

African (AFR)

AF:

0.143

AC:

3326

AN:

23326

American (AMR)

AF:

0.00990

AC:

AN:

9192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15450

East Asian (EAS)

AF:

0.00

AC:

AN:

26868

South Asian (SAS)

AF:

0.000446

AC:

AN:

35894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24922

Middle Eastern (MID)

AF:

0.00644

AC:

AN:

3108

European-Non Finnish (NFE)

AF:

0.000270

AC:

257

AN:

953218

Other (OTH)

AF:

0.00835

AC:

384

AN:

45978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

204

408

613

817

1021

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0379

AC:

5758

AN:

152006

Hom.:

377

Cov.:

AF XY:

0.0370

AC XY:

2748

AN XY:

74298

show subpopulations

African (AFR)

AF:

0.132

AC:

5475

AN:

41500

American (AMR)

AF:

0.0109

AC:

167

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10544

Middle Eastern (MID)

AF:

0.0103

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000560

AC:

AN:

67914

Other (OTH)

AF:

0.0332

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0303

Hom.:

Bravo

AF:

0.0431

Asia WGS

AF:

0.00377

AC:

AN:

3462

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Jul 08, 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.

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:1

May 28, 2019

GeneDx

Significance: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

-0.89

CADD

Benign

6.2

(source)

DANN

Benign

0.85

PhyloP100

-0.10

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

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

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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