7-726742-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017802.4(DNAAF5):c.22G>C(p.Glu8Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000723 in 1,244,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08854112).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.22G>C	p.Glu8Gln	missense_variant	1/13	ENST00000297440.11
PRKAR1B	NM_001164760.2	c.-23+468C>G		intron_variant		ENST00000537384.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.22G>C	p.Glu8Gln	missense_variant	1/13	1	NM_017802.4	P1
PRKAR1B	ENST00000537384.6	c.-23+468C>G		intron_variant		5	NM_001164760.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1092700 Hom.: 0 Cov.: 31 AF XY: 0.00000386 AC XY: 2 AN XY: 518224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000431

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74324

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 654564). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.03%). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 8 of the DNAAF5 protein (p.Glu8Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	14
Dann	Benign	0.92
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.087	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.048
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.045	D
Polyphen		0.047	B
Vest4		0.071
MutPred		0.18		Gain of catalytic residue at E8 (P = 0.1005);
MVP		0.030
MPC		0.16
ClinPred		0.42	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.48

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

LitVar

Other links and lift over

dbSNP: rs1337745093; hg19: chr7-766379;