7-726789-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_017802.4(DNAAF5):c.69G>T(p.Glu23Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,283,428 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 2 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.258

Variant links:

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]

DNAAF5 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015582144).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000723 (11/152094) while in subpopulation EAS AF= 0.00214 (11/5152). AF 95% confidence interval is 0.0012. There are 0 homozygotes in gnomad4. There are 6 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF5	NM_017802.4 link	c.69G>T	p.Glu23Asp	missense_variant	Exon 1 of 13	ENST00000297440.11	NP_060272.3	Q86Y56-1B3KPE2
PRKAR1B	NM_001164760.2 link	c.-23+421C>A		intron_variant	Intron 1 of 10	ENST00000537384.6	NP_001158232.1	P31321

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11 link	c.69G>T	p.Glu23Asp	missense_variant	Exon 1 of 13	1	NM_017802.4	ENSP00000297440.6		Q86Y56-1
PRKAR1B	ENST00000537384.6 link	c.-23+421C>A		intron_variant	Intron 1 of 10	5	NM_001164760.2	ENSP00000440449.1		P31321

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00213

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

GnomAD3 exomes

AF:

0.000243

AC:

AN:

4114

Hom.:

AF XY:

0.00

AC XY:

AN XY:

2592

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0250

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000191

AC:

216

AN:

1131334

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

112

AN XY:

542446

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00794

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000105

Gnomad4 OTH exome

AF:

0.0000438

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00214

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000102

ExAC

AF:

0.0000902

AC:

Asia WGS

AF:

0.00145

AC:

AN:

3466

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Jan 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 23 of the DNAAF5 protein (p.Glu23Asp). This variant is present in population databases (rs540763017, gnomAD 0.1%). 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: 1367513). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E23D variant (also known as c.69G>T), located in coding exon 1 of the DNAAF5 gene, results from a G to T substitution at nucleotide position 69. The glutamic acid at codon 23 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.2

DANN

Benign

0.74

DEOGEN2

Benign

0.024

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.0069

LIST_S2

Benign

0.32

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.43

REVEL

Benign

0.023

Sift

Benign

0.54

Sift4G

Benign

0.39

Polyphen

0.12

Vest4

0.054

MutPred

0.16

Loss of helix (P = 0.0167);

MVP

0.030

MPC

0.14

ClinPred

0.052

GERP RS

-0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.044

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over