rs9989177

chr14-49625753-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.44

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]

ACMG classification

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	UniProt
DNAAF2	NM_018139.3	c.2303A>G	p.Asp768Gly	missense_variant	3/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.2159A>G	p.Asp720Gly	missense_variant	2/2
DNAAF2	NM_001378453.1	c.92A>G	p.Asp31Gly	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.2303A>G	p.Asp768Gly	missense_variant	3/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.2159A>G	p.Asp720Gly	missense_variant	2/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.410 AC: 62300 AN: 152002 Hom.: 14933 Cov.: 32

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

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.: 45 AF XY: 0.506 AC XY: 367573 AN XY: 726018

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.: 32 AF XY: 0.411 AC XY: 30544 AN XY: 74370

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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. -

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	Invitae	Jan 31, 2024	- -

not specified Benign:2

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). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Congenital disorder of glycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.062	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.000060	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
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	T
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

Other links and lift over

dbSNP: rs9989177; hg19: chr14-50092471; COSMIC: COSV53568217; COSMIC: COSV53568217;