rs1337745093

Variant names:

• chr7-726742-G-C
• rs1337745093
• NM_017802.4:c.22G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. 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. 14/21 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
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08854112).

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.22G>C	p.Glu8Gln	missense	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+468C>G		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+848C>G		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.22G>C	p.Glu8Gln	missense	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+468C>G		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+848C>G		intron	N/A	ENSP00000385349.1	P31321

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 22936

American (AMR) AF: 0.00 AC: 0 AN: 8422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14514

East Asian (EAS) AF: 0.00 AC: 0 AN: 26582

South Asian (SAS) AF: 0.00 AC: 0 AN: 23438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3106

European-Non Finnish (NFE) AF: 0.00000431 AC: 4 AN: 927832

Other (OTH) AF: 0.00 AC: 0 AN: 44072

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0261725), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.0000965 AC: 4 AN: 41460

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

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	0.11
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
PhyloP100		4.0
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
PromoterAI		-0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.15
gMVP		0.48
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: rs1337745093; hg19: chr7-766379;