Genetic Variant DNAAF5:p.Gln147Leu (chr7-727160-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_017802.4(DNAAF5):c.440A>T(p.Gln147Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000877 in 1,139,864 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q147R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.8e-7 ( 0 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.92

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF5	NM_017802.4 link	c.440A>T	p.Gln147Leu	missense_variant	Exon 1 of 13	ENST00000297440.11	NP_060272.3	Q86Y56-1B3KPE2
PRKAR1B	NM_001164760.2 link	c.-23+50T>A		intron_variant	Intron 1 of 10	ENST00000537384.6	NP_001158232.1	P31321

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11 link	c.440A>T	p.Gln147Leu	missense_variant	Exon 1 of 13	1	NM_017802.4	ENSP00000297440.6		Q86Y56-1
PRKAR1B	ENST00000537384.6 link	c.-23+50T>A		intron_variant	Intron 1 of 10	5	NM_001164760.2	ENSP00000440449.1		P31321

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.77e-7

AC:

AN:

1139864

Hom.:

Cov.:

AF XY:

0.00000180

AC XY:

AN XY:

556252

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22628

American (AMR)

AF:

0.00

AC:

AN:

13702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16322

East Asian (EAS)

AF:

0.00

AC:

AN:

22826

South Asian (SAS)

AF:

0.00

AC:

AN:

45274

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24072

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3032

European-Non Finnish (NFE)

AF:

0.00000106

AC:

AN:

947798

Other (OTH)

AF:

0.00

AC:

AN:

44210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.21

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.80

PhyloP100

5.9

PrimateAI

Pathogenic

0.96

PROVEAN

Uncertain

-3.2

REVEL

Benign

0.21

Sift

Benign

0.035

Sift4G

Uncertain

0.0070

Polyphen

0.68

Vest4

0.35

MutPred

0.43

Gain of stability (P = 0.0955);

MVP

0.40

MPC

0.45

ClinPred

0.61

GERP RS

1.9

PromoterAI

0.035

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

4.0

Varity_R

0.12

gMVP

0.59

Mutation Taster

=84/16

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over