Genetic Variant DNAAF5:p.Leu149Leu (chr7-727167-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_017802.4(DNAAF5):c.447G>A(p.Leu149Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000858 in 1,165,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L149L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.6e-7 ( 0 hom. )

Consequence

DNAAF5
NM_017802.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.172

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: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.94).

BP7

Synonymous conserved (PhyloP=0.172 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF5	NM_017802.4 link	c.447G>A	p.Leu149Leu	synonymous_variant	Exon 1 of 13	ENST00000297440.11	NP_060272.3
PRKAR1B	NM_001164760.2 link	c.-23+43C>T		intron_variant	Intron 1 of 10	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11 link	c.447G>A	p.Leu149Leu	synonymous_variant	Exon 1 of 13	1	NM_017802.4	ENSP00000297440.6
PRKAR1B	ENST00000537384.6 link	c.-23+43C>T		intron_variant	Intron 1 of 10	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.58e-7

AC:

AN:

1165160

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

570478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23206

American (AMR)

AF:

0.00

AC:

AN:

16106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17398

East Asian (EAS)

AF:

0.0000429

AC:

AN:

23292

South Asian (SAS)

AF:

0.00

AC:

AN:

50680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3150

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

960314

Other (OTH)

AF:

0.00

AC:

AN:

45432

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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

3.4

(source)

DANN

Benign

0.87

PhyloP100

0.17

PromoterAI

0.088

Neutral

(source)

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over