7-726764-C-T

Variant names:

• chr7-726764-C-T
• rs1781309439
• NM_017802.4:c.44C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017802.4(DNAAF5):​c.44C>T​(p.Pro15Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0120
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06813282).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	NM_017802.4	MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+446G>A		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+826G>A		intron	N/A	NP_001158230.1	P31321

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF5	ENST00000297440.11	TSL:1 MANE Select	c.44C>T	p.Pro15Leu	missense	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+446G>A		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+826G>A		intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1106760 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 526898

African (AFR) AF: 0.00 AC: 0 AN: 23022

American (AMR) AF: 0.00 AC: 0 AN: 8486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14712

East Asian (EAS) AF: 0.00 AC: 0 AN: 26672

South Asian (SAS) AF: 0.00 AC: 0 AN: 27508

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3054

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 935854

Other (OTH) AF: 0.00 AC: 0 AN: 44676

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.49	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.068	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.012
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.043
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0040	B
Vest4		0.16
MutPred		0.22		Loss of loop (P = 9e-04)
MVP		0.067
MPC		0.16
ClinPred		0.16	T
GERP RS		0.18
PromoterAI		-0.18	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.062
gMVP		0.33
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1781309439; hg19: chr7-766401;