rs52814244

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.1505C>T(p.Pro502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,566 control chromosomes in the GnomAD database, including 107,765 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 0.31 ( 7769 hom., cov: 32)

Exomes 𝑓: 0.37 ( 99996 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.826

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=8.3488226E-4).

BP6

Variant 16-84170333-C-T is Benign according to our data. Variant chr16-84170333-C-T is described in ClinVar as [Benign]. Clinvar id is 226575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170333-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 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.1505C>T	p.Pro502Leu	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.1505C>T	p.Pro502Leu	missense_variant	8/12	1	NM_178452.6	ENSP00000367815.5		Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.307

AC:

46589

AN:

151974

Hom.:

7761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.469

Gnomad AMR

AF:

0.366

Gnomad ASJ

AF:

0.364

Gnomad EAS

AF:

0.329

Gnomad SAS

AF:

0.288

Gnomad FIN

AF:

0.339

Gnomad MID

AF:

0.288

Gnomad NFE

AF:

0.372

Gnomad OTH

AF:

0.318

GnomAD3 exomes

AF:

0.344

AC:

85585

AN:

248686

Hom.:

15240

AF XY:

0.345

AC XY:

46532

AN XY:

134970

show subpopulations

Gnomad AFR exome

AF:

0.152

Gnomad AMR exome

AF:

0.384

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.341

Gnomad SAS exome

AF:

0.287

Gnomad FIN exome

AF:

0.340

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.349

GnomAD4 exome

AF:

0.367

AC:

535884

AN:

1461474

Hom.:

99996

Cov.:

AF XY:

0.364

AC XY:

264345

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.151

Gnomad4 AMR exome

AF:

0.383

Gnomad4 ASJ exome

AF:

0.359

Gnomad4 EAS exome

AF:

0.331

Gnomad4 SAS exome

AF:

0.286

Gnomad4 FIN exome

AF:

0.339

Gnomad4 NFE exome

AF:

0.383

Gnomad4 OTH exome

AF:

0.348

GnomAD4 genome

AF:

0.306

AC:

46609

AN:

152092

Hom.:

7769

Cov.:

AF XY:

0.306

AC XY:

22780

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.160

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.364

Gnomad4 EAS

AF:

0.330

Gnomad4 SAS

AF:

0.288

Gnomad4 FIN

AF:

0.339

Gnomad4 NFE

AF:

0.372

Gnomad4 OTH

AF:

0.315

Alfa

AF:

0.363

Hom.:

16696

Bravo

AF:

0.306

TwinsUK

AF:

0.390

AC:

1445

ALSPAC

AF:

0.383

AC:

1477

ESP6500AA

AF:

0.160

AC:

700

ESP6500EA

AF:

0.370

AC:

3176

ExAC

AF:

0.338

AC:

40957

Asia WGS

AF:

0.269

AC:

933

AN:

3478

EpiCase

AF:

0.368

EpiControl

AF:

0.374

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2015	p.Pro502Leu in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 37.5% (24168/64438) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs11644164). -

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	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.29

DANN

Benign

0.23

DEOGEN2

Benign

0.0022

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0041

LIST_S2

Benign

0.36

MetaRNN

Benign

0.00083

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.81

PrimateAI

Benign

0.31

PROVEAN

Benign

0.14

REVEL

Benign

0.0060

Sift

Benign

0.53

Sift4G

Benign

0.40

Polyphen

0.0030

Vest4

0.049

MPC

0.020

ClinPred

0.00055

GERP RS

-0.20

Varity_R

0.019

gMVP

0.076

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