rs2288021

Positions:

chr16-84176209-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_178452.6(DNAAF1):c.1975C>G(p.Leu659Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,716 control chromosomes in the GnomAD database, including 34,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L659P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.16 ( 2577 hom., cov: 33)

Exomes 𝑓: 0.21 ( 32338 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.430

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 -16 ACMG points.

BP6

Variant 16-84176209-C-G is Benign according to our data. Variant chr16-84176209-C-G is described in ClinVar as [Benign]. Clinvar id is 163088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84176209-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 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.1975C>G	p.Leu659Val	missense_variant	11/12	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.1975C>G	p.Leu659Val	missense_variant	11/12	1	NM_178452.6	ENSP00000367815	P1	Q8NEP3-1

Frequencies

GnomAD3 genomes

AF:

0.164

AC:

24898

AN:

152118

Hom.:

2576

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0412

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.203

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.112

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.220

Gnomad OTH

AF:

0.186

GnomAD3 exomes

AF:

0.199

AC:

50022

AN:

250950

Hom.:

5316

AF XY:

0.202

AC XY:

27400

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.0375

Gnomad AMR exome

AF:

0.220

Gnomad ASJ exome

AF:

0.226

Gnomad EAS exome

AF:

0.120

Gnomad SAS exome

AF:

0.212

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.220

Gnomad OTH exome

AF:

0.207

GnomAD4 exome

AF:

0.207

AC:

302398

AN:

1461480

Hom.:

32338

Cov.:

AF XY:

0.208

AC XY:

150975

AN XY:

727048

show subpopulations

Gnomad4 AFR exome

AF:

0.0357

Gnomad4 AMR exome

AF:

0.217

Gnomad4 ASJ exome

AF:

0.220

Gnomad4 EAS exome

AF:

0.0975

Gnomad4 SAS exome

AF:

0.214

Gnomad4 FIN exome

AF:

0.211

Gnomad4 NFE exome

AF:

0.214

Gnomad4 OTH exome

AF:

0.204

GnomAD4 genome

AF:

0.164

AC:

24891

AN:

152236

Hom.:

2577

Cov.:

AF XY:

0.162

AC XY:

12030

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0411

Gnomad4 AMR

AF:

0.203

Gnomad4 ASJ

AF:

0.224

Gnomad4 EAS

AF:

0.111

Gnomad4 SAS

AF:

0.208

Gnomad4 FIN

AF:

0.202

Gnomad4 NFE

AF:

0.220

Gnomad4 OTH

AF:

0.186

Alfa

AF:

0.208

Hom.:

1129

Bravo

AF:

0.159

TwinsUK

AF:

0.207

AC:

768

ALSPAC

AF:

0.201

AC:

775

ESP6500AA

AF:

0.0436

AC:

192

ESP6500EA

AF:

0.218

AC:

1878

ExAC

AF:

0.197

AC:

23939

Asia WGS

AF:

0.137

AC:

476

AN:

3478

EpiCase

AF:

0.221

EpiControl

AF:

0.221

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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	Feb 21, 2013	Leu659Val in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 21.8% (1878/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2288021). -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 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 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 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

0.085

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

4.1

DANN

Benign

0.89

DEOGEN2

Benign

0.0058

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.31

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.25

PROVEAN

Benign

0.17

N;N

REVEL

Benign

0.032

Sift

Uncertain

0.022

D;T

Sift4G

Benign

0.093

T;T

Polyphen

0.013

B;.

Vest4

0.020

MPC

0.020

ClinPred

0.0023

GERP RS

0.29

Varity_R

0.049

gMVP

0.059

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -1

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