rs9989177

Positions:

chr14-49625753-T-C

Variant summary

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

The NM_018139.3(DNAAF2):c.2303A>G(p.Asp768Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.496 in 1,611,812 control chromosomes in the GnomAD database, including 208,461 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 14938 hom., cov: 32)

Exomes 𝑓: 0.50 ( 193523 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.44

Variant links:

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

DNAAF2 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=6.0439936E-5).

BP6

Variant 14-49625753-T-C is Benign according to our data. Variant chr14-49625753-T-C is described in ClinVar as [Benign]. Clinvar id is 163091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-49625753-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAAF2	NM_018139.3 linkuse as main transcript	c.2303A>G	p.Asp768Gly	missense_variant	3/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2 linkuse as main transcript	c.2159A>G	p.Asp720Gly	missense_variant	2/2		NP_001077377.1
DNAAF2	NM_001378453.1 linkuse as main transcript	c.92A>G	p.Asp31Gly	missense_variant	2/2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13 linkuse as main transcript	c.2303A>G	p.Asp768Gly	missense_variant	3/3	1	NM_018139.3	ENSP00000298292	P2	Q9NVR5-1
DNAAF2	ENST00000406043.3 linkuse as main transcript	c.2159A>G	p.Asp720Gly	missense_variant	2/2	1		ENSP00000384862	A2	Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.410

AC:

62300

AN:

152002

Hom.:

14933

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.568

Gnomad AMR

AF:

0.351

Gnomad ASJ

AF:

0.565

Gnomad EAS

AF:

0.126

Gnomad SAS

AF:

0.479

Gnomad FIN

AF:

0.585

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.424

GnomAD3 exomes

AF:

0.445

AC:

110924

AN:

249242

Hom.:

27654

AF XY:

0.459

AC XY:

61853

AN XY:

134650

show subpopulations

Gnomad AFR exome

AF:

0.178

Gnomad AMR exome

AF:

0.267

Gnomad ASJ exome

AF:

0.576

Gnomad EAS exome

AF:

0.129

Gnomad SAS exome

AF:

0.486

Gnomad FIN exome

AF:

0.567

Gnomad NFE exome

AF:

0.541

Gnomad OTH exome

AF:

0.483

GnomAD4 exome

AF:

0.505

AC:

737044

AN:

1459690

Hom.:

193523

Cov.:

AF XY:

0.506

AC XY:

367573

AN XY:

726018

show subpopulations

Gnomad4 AFR exome

AF:

0.179

Gnomad4 AMR exome

AF:

0.279

Gnomad4 ASJ exome

AF:

0.574

Gnomad4 EAS exome

AF:

0.0987

Gnomad4 SAS exome

AF:

0.482

Gnomad4 FIN exome

AF:

0.568

Gnomad4 NFE exome

AF:

0.537

Gnomad4 OTH exome

AF:

0.474

GnomAD4 genome

AF:

0.410

AC:

62327

AN:

152122

Hom.:

14938

Cov.:

AF XY:

0.411

AC XY:

30544

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.187

Gnomad4 AMR

AF:

0.351

Gnomad4 ASJ

AF:

0.565

Gnomad4 EAS

AF:

0.126

Gnomad4 SAS

AF:

0.477

Gnomad4 FIN

AF:

0.585

Gnomad4 NFE

AF:

0.538

Gnomad4 OTH

AF:

0.427

Alfa

AF:

0.501

Hom.:

41945

Bravo

AF:

0.377

TwinsUK

AF:

0.546

AC:

2023

ALSPAC

AF:

0.544

AC:

2098

ESP6500AA

AF:

0.193

AC:

852

ESP6500EA

AF:

0.537

AC:

4620

ExAC

AF:

0.451

AC:

54694

Asia WGS

AF:

0.318

AC:

1103

AN:

3478

EpiCase

AF:

0.530

EpiControl

AF:

0.539

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 10

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 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. -
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:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
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	- -

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	Asp768Gly in exon 3 of DNAAF2: This variant is not expected to have clinical sig nificance because it has been identified in 46.3% (3980/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs9989177). -

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	-	- -

Congenital disorder of glycosylation

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.000060

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.089

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.037

D;D

Polyphen

0.65

P;P

Vest4

0.019

MPC

1.0

ClinPred

0.021

GERP RS

5.7

Varity_R

0.12

gMVP

0.22

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