rs998645747

Variant names:

• chr7-727102-C-T
• rs998645747
• NM_017802.4:c.382C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-727102-C-T
• chr7-727102-C-A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017802.4(DNAAF5):​c.382C>T​(p.Pro128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,084,758 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P128P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.418
• 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=0.13829139).

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.382C>T	p.Pro128Ser	missense	Exon 1 of 13	NP_060272.3
	PRKAR1B	NM_001164760.2	MANE Select	c.-23+108G>A		intron	N/A	NP_001158232.1	P31321
	PRKAR1B	NM_001164758.2		c.-23+488G>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.382C>T	p.Pro128Ser	missense	Exon 1 of 13	ENSP00000297440.6	Q86Y56-1
	PRKAR1B	ENST00000537384.6	TSL:5 MANE Select	c.-23+108G>A		intron	N/A	ENSP00000440449.1	P31321
	PRKAR1B	ENST00000403562.5	TSL:1	c.-23+488G>A		intron	N/A	ENSP00000385349.1	P31321

Frequencies

GnomAD3 genomes AF: 0.0000748 AC: 11 AN: 147048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000733

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000121

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 185 AN: 937710 Hom.: 0 Cov.: 30 AF XY: 0.000183 AC XY: 81 AN XY: 442408

African (AFR) AF: 0.00 AC: 0 AN: 18130

American (AMR) AF: 0.00 AC: 0 AN: 3882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8248

East Asian (EAS) AF: 0.00 AC: 0 AN: 11008

South Asian (SAS) AF: 0.00 AC: 0 AN: 19276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10142

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2156

European-Non Finnish (NFE) AF: 0.000220 AC: 183 AN: 831408

Other (OTH) AF: 0.0000598 AC: 2 AN: 33460

GnomAD4 genome AF: 0.0000748 AC: 11 AN: 147048 Hom.: 0 Cov.: 32 AF XY: 0.0000699 AC XY: 5 AN XY: 71540

African (AFR) AF: 0.0000733 AC: 3 AN: 40902

American (AMR) AF: 0.00 AC: 0 AN: 14818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3384

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8708

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

European-Non Finnish (NFE) AF: 0.000121 AC: 8 AN: 66068

Other (OTH) AF: 0.00 AC: 0 AN: 2028

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

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	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.93
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.00079	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.42
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.047
Sift	Benign	0.042	D
Sift4G	Benign	0.63	T
Polyphen		0.20	B
Vest4		0.081
MutPred		0.18		Gain of helix (P = 0.0325)
MVP		0.030
MPC		0.18
ClinPred		0.16	T
GERP RS		3.0
PromoterAI		-0.028	Neutral
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Varity_R		0.064
gMVP		0.41
Mutation Taster		=90/10	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: rs998645747; hg19: chr7-766739;