rs878855039

Variant names:

• chr7-727270-C-A
• rs878855039
• NM_001164760.2:c.-83G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001164760.2(PRKAR1B):​c.-83G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,325,432 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: PRKAR1B NM_001164760.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 1.60

Genes affected

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1319184).
• BS2: High AC in GnomAd4 at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PRKAR1B	NM_001164760.2	c.-83G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	ENST00000537384.6	NP_001158232.1
DNAAF5	NM_017802.4	c.550C>A	p.Arg184Ser	missense_variant	Exon 1 of 13	ENST00000297440.11	NP_060272.3
PRKAR1B	NM_001164760.2	c.-83G>T		5_prime_UTR_variant	Exon 1 of 11	ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PRKAR1B	ENST00000537384.6	c.-83G>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 11	5	NM_001164760.2	ENSP00000440449.1
DNAAF5	ENST00000297440.11	c.550C>A	p.Arg184Ser	missense_variant	Exon 1 of 13	1	NM_017802.4	ENSP00000297440.6
PRKAR1B	ENST00000537384.6	c.-83G>T		5_prime_UTR_variant	Exon 1 of 11	5	NM_001164760.2	ENSP00000440449.1

Frequencies

GnomAD3 genomes AF: 0.000397 AC: 60 AN: 151112 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.000460

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000667

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000612 AC: 6 AN: 9798 Hom.: 0 AF XY: 0.000841 AC XY: 5 AN XY: 5942

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00336

GnomAD4 exome AF: 0.000668 AC: 784 AN: 1174212 Hom.: 1 Cov.: 31 AF XY: 0.000670 AC XY: 382 AN XY: 570512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000375

Gnomad4 ASJ exome AF: 0.0000622

Gnomad4 EAS exome AF: 0.0000383

Gnomad4 SAS exome AF: 0.000390

Gnomad4 FIN exome AF: 0.0000371

Gnomad4 NFE exome AF: 0.000746

Gnomad4 OTH exome AF: 0.000551

GnomAD4 genome AF: 0.000397 AC: 60 AN: 151220 Hom.: 0 Cov.: 32 AF XY: 0.000338 AC XY: 25 AN XY: 73870

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000460

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000668

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000540 Hom.: 0

Bravo AF: 0.000404

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 184 of the DNAAF5 protein (p.Arg184Ser). This variant is present in population databases (no rsID available, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 241208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAAF5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 10, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia 18 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Benign	0.94
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.10
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.011	D
Polyphen		0.70	P
Vest4		0.38
MutPred		0.47		Loss of helix (P = 0.0237);
MVP		0.048
MPC		0.55
ClinPred		0.12	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.27
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs878855039; hg19: chr7-766907;