chr7-727160-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017802.4(DNAAF5):​c.440A>G​(p.Gln147Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000135 in 148,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29106647).

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>G	p.Gln147Arg	missense	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+50T>C		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+430T>C		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>G	p.Gln147Arg	missense	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+50T>C		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+430T>C		intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000134

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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1139864 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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: 0.00 AC: 0 AN: 947798

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

GnomAD4 genome AF: 0.0000135 AC: 2 AN: 148052 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 1 AN XY: 72138

African (AFR) AF: 0.00 AC: 0 AN: 40602

American (AMR) AF: 0.000134 AC: 2 AN: 14936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3396

East Asian (EAS) AF: 0.00 AC: 0 AN: 5020

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66540

Other (OTH) AF: 0.00 AC: 0 AN: 2036

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Primary ciliary dyskinesia (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Benign	0.51
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.9
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.16
Sift	Benign	0.14	T
Sift4G	Uncertain	0.012	D
Polyphen		0.0060	B
Vest4		0.30
MutPred		0.45		Gain of disorder (P = 0.0497)
MVP		0.11
MPC		0.37
ClinPred		0.50	D
GERP RS		1.9
PromoterAI		0.056	Neutral
Varity_R		0.088
gMVP		0.50
Mutation Taster		=94/6	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;