7-727160-A-T

Variant names:

• chr7-727160-A-T
• rs878855038
• NM_017802.4:c.440A>T

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.440A>T	p.Gln147Leu	missense	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+50T>A		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+430T>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.440A>T	p.Gln147Leu	missense	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+50T>A		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+430T>A		intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.77e-7 AC: 1 AN: 1139864 Hom.: 0 Cov.: 31 AF XY: 0.00000180 AC XY: 1 AN XY: 556252

African (AFR) AF: 0.00 AC: 0 AN: 22628

American (AMR) AF: 0.00 AC: 0 AN: 13702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16322

East Asian (EAS) AF: 0.00 AC: 0 AN: 22826

South Asian (SAS) AF: 0.00 AC: 0 AN: 45274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3032

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 947798

Other (OTH) AF: 0.00 AC: 0 AN: 44210

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	21
DANN	Benign	0.87
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.80	T
PhyloP100		5.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.21
Sift	Benign	0.035	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.68	P
Vest4		0.35
MutPred		0.43		Gain of stability (P = 0.0955)
MVP		0.40
MPC		0.45
ClinPred		0.61	D
GERP RS		1.9
PromoterAI		0.035	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		4.0
Varity_R		0.12
gMVP		0.59
Mutation Taster		=84/16	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: rs878855038; hg19: chr7-766797;