rs56964619

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.1296G>C(p.Glu432Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 1,605,926 control chromosomes in the GnomAD database, including 7,175 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 0.079 ( 514 hom., cov: 32)

Exomes 𝑓: 0.088 ( 6661 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.933

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:

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=0.00406757).

BP6

Variant 16-84170124-G-C is Benign according to our data. Variant chr16-84170124-G-C is described in ClinVar as [Benign]. Clinvar id is 226573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170124-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.189 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.1296G>C	p.Glu432Asp	missense_variant	8/12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10 linkuse as main transcript	c.1296G>C	p.Glu432Asp	missense_variant	8/12	1	NM_178452.6	ENSP00000367815	P1	Q8NEP3-1
DNAAF1	ENST00000563818.5 linkuse as main transcript	n.973G>C		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5 linkuse as main transcript	n.1450G>C		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5 linkuse as main transcript	c.1225+71G>C		intron_variant, NMD_transcript_variant		2		ENSP00000457373		Q8NEP3-3

Frequencies

GnomAD3 genomes

AF:

0.0790

AC:

11995

AN:

151784

Hom.:

512

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0572

Gnomad AMI

AF:

0.131

Gnomad AMR

AF:

0.0587

Gnomad ASJ

AF:

0.103

Gnomad EAS

AF:

0.139

Gnomad SAS

AF:

0.198

Gnomad FIN

AF:

0.0707

Gnomad MID

AF:

0.0764

Gnomad NFE

AF:

0.0830

Gnomad OTH

AF:

0.0891

GnomAD3 exomes

AF:

0.0945

AC:

23744

AN:

251252

Hom.:

1468

AF XY:

0.101

AC XY:

13780

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.0577

Gnomad AMR exome

AF:

0.0439

Gnomad ASJ exome

AF:

0.104

Gnomad EAS exome

AF:

0.123

Gnomad SAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.0752

Gnomad NFE exome

AF:

0.0836

Gnomad OTH exome

AF:

0.0923

GnomAD4 exome

AF:

0.0885

AC:

128618

AN:

1454026

Hom.:

6661

Cov.:

100

AF XY:

0.0924

AC XY:

66852

AN XY:

723348

show subpopulations

Gnomad4 AFR exome

AF:

0.0556

Gnomad4 AMR exome

AF:

0.0464

Gnomad4 ASJ exome

AF:

0.106

Gnomad4 EAS exome

AF:

0.152

Gnomad4 SAS exome

AF:

0.202

Gnomad4 FIN exome

AF:

0.0748

Gnomad4 NFE exome

AF:

0.0798

Gnomad4 OTH exome

AF:

0.0963

GnomAD4 genome

AF:

0.0791

AC:

12014

AN:

151900

Hom.:

514

Cov.:

AF XY:

0.0809

AC XY:

6009

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0574

Gnomad4 AMR

AF:

0.0586

Gnomad4 ASJ

AF:

0.103

Gnomad4 EAS

AF:

0.138

Gnomad4 SAS

AF:

0.199

Gnomad4 FIN

AF:

0.0707

Gnomad4 NFE

AF:

0.0830

Gnomad4 OTH

AF:

0.0919

Alfa

AF:

0.0701

Hom.:

167

Bravo

AF:

0.0756

TwinsUK

AF:

0.0863

AC:

320

ALSPAC

AF:

0.0786

AC:

303

ESP6500AA

AF:

0.0559

AC:

246

ESP6500EA

AF:

0.0844

AC:

726

ExAC

AF:

0.0971

AC:

11783

Asia WGS

AF:

0.183

AC:

636

AN:

3478

EpiCase

AF:

0.0863

EpiControl

AF:

0.0859

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 12, 2015	p.Glu432Asp in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 20% (3315/16512) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs9972733). -

Primary ciliary dyskinesia 13

Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.58

DANN

Benign

0.76

DEOGEN2

Benign

0.0057

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0053

LIST_S2

Benign

0.50

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.63

REVEL

Benign

0.019

Sift

Benign

0.099

Sift4G

Benign

0.61

Polyphen

0.0

Vest4

0.022

MutPred

0.11

Loss of methylation at K430 (P = 0.0922);

MPC

0.019

ClinPred

0.0057

GERP RS

0.70

Varity_R

0.084

gMVP

0.075

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