rs1039028606

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_017802.4(DNAAF5):c.289G>A(p.Val97Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000647 in 1,236,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V97V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27614796).

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.289G>A	p.Val97Met	missense	Exon 1 of 13	NP_060272.3
PRKAR1B	NM_001164760.2	MANE Select	c.-23+201C>T		intron	N/A	NP_001158232.1
DNAAF5	NR_075098.2		n.311G>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.289G>A	p.Val97Met	missense	Exon 1 of 13	ENSP00000297440.6
PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+201C>T		intron	N/A	ENSP00000440449.1
PRKAR1B	ENST00000403562.5	TSL:1	c.-23+581C>T		intron	N/A	ENSP00000385349.1

Frequencies

GnomAD3 genomes

AF:

0.0000201

AC:

AN:

148940

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000487

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000460

AC:

AN:

1087244

Hom.:

Cov.:

AF XY:

0.00000763

AC XY:

AN XY:

524134

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21290

American (AMR)

AF:

0.00

AC:

AN:

8796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13190

East Asian (EAS)

AF:

0.00

AC:

AN:

21234

South Asian (SAS)

AF:

0.0000794

AC:

AN:

37762

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22090

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2774

European-Non Finnish (NFE)

AF:

0.00000218

AC:

AN:

918524

Other (OTH)

AF:

0.00

AC:

AN:

41584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0324306), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.385

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

AF:

0.0000201

AC:

AN:

148940

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72626

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41048

American (AMR)

AF:

0.00

AC:

AN:

14990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

66902

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.047

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.55

M_CAP

Pathogenic

0.65

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.84

PhyloP100

1.2

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.4

REVEL

Benign

0.078

Sift

Uncertain

0.029

Sift4G

Benign

0.064

Polyphen

0.84

Vest4

0.17

MutPred

0.41

Gain of catalytic residue at V97 (P = 0.0457)

MVP

0.12

MPC

0.35

ClinPred

0.45

GERP RS

2.5

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.2

Varity_R

0.083

gMVP

0.41

Mutation Taster

=95/5

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

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over