rs112044935

Positions:

chr14-49634422-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_018139.3(DNAAF2):c.728A>C(p.Glu243Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,569,868 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E243K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0059 ( 12 hom., cov: 33)

Exomes 𝑓: 0.00060 ( 12 hom. )

Consequence

DNAAF2
NM_018139.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.622

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=0.0028954148).

BP6

Variant 14-49634422-T-G is Benign according to our data. Variant chr14-49634422-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 261022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00588 (894/152098) while in subpopulation AFR AF= 0.0206 (856/41524). AF 95% confidence interval is 0.0195. There are 12 homozygotes in gnomad4. There are 405 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3 linkuse as main transcript	c.728A>C	p.Glu243Ala	missense_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2 linkuse as main transcript	c.728A>C	p.Glu243Ala	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13 linkuse as main transcript	c.728A>C	p.Glu243Ala	missense_variant	1/3	1	NM_018139.3	P2	Q9NVR5-1
DNAAF2	ENST00000406043.3 linkuse as main transcript	c.728A>C	p.Glu243Ala	missense_variant	1/2	1		A2	Q9NVR5-2

Frequencies

GnomAD3 genomes

AF:

0.00585

AC:

889

AN:

151980

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0206

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00145

AC:

268

AN:

184552

Hom.:

AF XY:

0.00125

AC XY:

128

AN XY:

102742

show subpopulations

Gnomad AFR exome

AF:

0.0207

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000877

Gnomad OTH exome

AF:

0.00123

GnomAD4 exome

AF:

0.000604

AC:

857

AN:

1417770

Hom.:

Cov.:

AF XY:

0.000567

AC XY:

398

AN XY:

701406

show subpopulations

Gnomad4 AFR exome

AF:

0.0190

Gnomad4 AMR exome

AF:

0.00139

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000250

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000541

Gnomad4 OTH exome

AF:

0.00157

GnomAD4 genome

AF:

0.00588

AC:

894

AN:

152098

Hom.:

Cov.:

AF XY:

0.00545

AC XY:

405

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.0206

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00183

Hom.:

Bravo

AF:

0.00617

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.000132

AC:

ExAC

AF:

0.00138

AC:

161

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 08, 2015	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 25, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Primary ciliary dyskinesia 10

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.3

DANN

Benign

0.87

DEOGEN2

Benign

0.0054

T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

0.0029

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.027

Sift

Benign

0.31

T;T

Sift4G

Uncertain

0.041

D;D

Polyphen

0.0040

B;B

Vest4

0.14

MVP

0.21

MPC

0.83

ClinPred

0.013

GERP RS

-0.13

Varity_R

0.12

gMVP

0.42

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