rs17856705

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_178452.6(DNAAF1):c.1178A>G(p.Lys393Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,613,638 control chromosomes in the GnomAD database, including 158,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.38 ( 11560 hom., cov: 33)

Exomes 𝑓: 0.44 ( 147044 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0210

Variant links:

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

DNAAF1 links:

DNAAF1 (HGNC:):

DNAAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.163822E-4).

BP6

Variant 16-84170006-A-G is Benign according to our data. Variant chr16-84170006-A-G is described in ClinVar as [Benign]. Clinvar id is 226572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170006-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6 linkuse as main transcript	c.1178A>G	p.Lys393Arg	missense_variant	8/12	ENST00000378553.10	NP_848547.4	Q8NEP3-1A0A140VJN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.1178A>G	p.Lys393Arg	missense_variant	8/12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.377

AC:

57381

AN:

152070

Hom.:

11549

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.487

Gnomad AMR

AF:

0.404

Gnomad ASJ

AF:

0.386

Gnomad EAS

AF:

0.332

Gnomad SAS

AF:

0.304

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.313

Gnomad NFE

AF:

0.460

Gnomad OTH

AF:

0.368

GnomAD3 exomes

AF:

0.402

AC:

101023

AN:

251180

Hom.:

21103

AF XY:

0.402

AC XY:

54566

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.411

Gnomad ASJ exome

AF:

0.381

Gnomad EAS exome

AF:

0.342

Gnomad SAS exome

AF:

0.306

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.456

Gnomad OTH exome

AF:

0.408

GnomAD4 exome

AF:

0.444

AC:

649027

AN:

1461448

Hom.:

147044

Cov.:

AF XY:

0.439

AC XY:

319329

AN XY:

727012

show subpopulations

Gnomad4 AFR exome

AF:

0.217

Gnomad4 AMR exome

AF:

0.411

Gnomad4 ASJ exome

AF:

0.383

Gnomad4 EAS exome

AF:

0.332

Gnomad4 SAS exome

AF:

0.306

Gnomad4 FIN exome

AF:

0.443

Gnomad4 NFE exome

AF:

0.471

Gnomad4 OTH exome

AF:

0.414

GnomAD4 genome

AF:

0.377

AC:

57415

AN:

152190

Hom.:

11560

Cov.:

AF XY:

0.375

AC XY:

27891

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.227

Gnomad4 AMR

AF:

0.405

Gnomad4 ASJ

AF:

0.386

Gnomad4 EAS

AF:

0.332

Gnomad4 SAS

AF:

0.304

Gnomad4 FIN

AF:

0.444

Gnomad4 NFE

AF:

0.460

Gnomad4 OTH

AF:

0.364

Alfa

AF:

0.433

Hom.:

31504

Bravo

AF:

0.369

TwinsUK

AF:

0.476

AC:

1764

ALSPAC

AF:

0.473

AC:

1822

ESP6500AA

AF:

0.225

AC:

991

ESP6500EA

AF:

0.457

AC:

3932

ExAC

AF:

0.400

AC:

48528

Asia WGS

AF:

0.286

AC:

994

AN:

3478

EpiCase

AF:

0.442

EpiControl

AF:

0.445

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 05, 2015	p.Lys393Arg in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance it has been identified in 45% (30157/66644) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs17856705). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Primary ciliary dyskinesia 13

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.1

DANN

Benign

0.67

DEOGEN2

Benign

0.0066

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.41

MetaRNN

Benign

0.00012

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.48

REVEL

Benign

0.055

Sift

Benign

0.22

Sift4G

Benign

0.44

Polyphen

0.0010

Vest4

0.025

MPC

0.019

ClinPred

0.0016

GERP RS

0.13

Varity_R

0.025

gMVP

0.055

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