rs1031852692

Positions:

• chr7-727105-G-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

The NM_017802.4(DNAAF5):​c.385G>C​(p.Val129Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,093,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.50

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03114456).
• BP6: Variant 7-727105-G-C is Benign according to our data. Variant chr7-727105-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 454867.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000898 (132/146978) while in subpopulation NFE AF= 0.00176 (116/66032). AF 95% confidence interval is 0.0015. There are 0 homozygotes in gnomad4. There are 51 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.385G>C	p.Val129Leu	missense_variant	1/13	ENST00000297440.11	NP_060272.3
PRKAR1B	NM_001164760.2	c.-23+105C>G		intron_variant		ENST00000537384.6	NP_001158232.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.385G>C	p.Val129Leu	missense_variant	1/13	1	NM_017802.4	ENSP00000297440	P1
PRKAR1B	ENST00000537384.6	c.-23+105C>G		intron_variant		5	NM_001164760.2	ENSP00000440449	P1

Frequencies

GnomAD3 genomes AF: 0.000899 AC: 132 AN: 146872 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000405

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000346

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.000493

GnomAD4 exome AF: 0.00151 AC: 1425 AN: 946650 Hom.: 0 Cov.: 30 AF XY: 0.00153 AC XY: 683 AN XY: 446936

Gnomad4 AFR exome AF: 0.000109

Gnomad4 AMR exome AF: 0.000243

Gnomad4 ASJ exome AF: 0.00105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000515

Gnomad4 FIN exome AF: 0.000994

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.000618

GnomAD4 genome AF: 0.000898 AC: 132 AN: 146978 Hom.: 0 Cov.: 32 AF XY: 0.000713 AC XY: 51 AN XY: 71540

Gnomad4 AFR AF: 0.0000488

Gnomad4 AMR AF: 0.000405

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000346

Gnomad4 NFE AF: 0.00176

Gnomad4 OTH AF: 0.000487

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.000971

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 21, 2022	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 129 of the DNAAF5 protein (p.Val129Leu). This variant is present in population databases (no rsID available, gnomAD 0.4%), 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: 454867). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 06, 2017	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

PRKAR1B: BS1, BS2 -

DNAAF5-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	15
DANN	Benign	0.62
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.034
Sift	Benign	0.34	T
Sift4G	Benign	0.32	T
Polyphen		0.0090	B
Vest4		0.038
MutPred		0.21		Gain of glycosylation at P130 (P = 0.1328);
MVP		0.014
MPC		0.16
ClinPred		0.25	T
GERP RS		1.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.3
Varity_R		0.038
gMVP		0.40

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: rs1031852692; hg19: chr7-766742;