rs200775946

Positions:

chr19-55161145-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001256715.2(DNAAF3):c.832G>A(p.Ala278Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00245 in 1,553,668 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

DNAAF3
NM_001256715.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

DNAAF3 links:

DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

DNAAF3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013263226).

BP6

Variant 19-55161145-C-T is Benign according to our data. Variant chr19-55161145-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 330215.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}. Variant chr19-55161145-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (292/152286) while in subpopulation NFE AF= 0.003 (204/68016). AF 95% confidence interval is 0.00266. There are 2 homozygotes in gnomad4. There are 149 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2 linkuse as main transcript	c.832G>A	p.Ala278Thr	missense_variant	8/12	ENST00000524407.7	NP_001243644.1
DNAAF3-AS1	XR_007067344.1 linkuse as main transcript	n.237C>T		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7 linkuse as main transcript	c.832G>A	p.Ala278Thr	missense_variant	8/12	1	NM_001256715.2	ENSP00000432046	A2	Q8N9W5-1
DNAAF3-AS1	ENST00000591665.1 linkuse as main transcript	n.1067C>T		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes

AF:

0.00192

AC:

292

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00433

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00300

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00172

AC:

270

AN:

156806

Hom.:

AF XY:

0.00162

AC XY:

137

AN XY:

84474

show subpopulations

Gnomad AFR exome

AF:

0.000253

Gnomad AMR exome

AF:

0.000790

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000266

Gnomad SAS exome

AF:

0.00128

Gnomad FIN exome

AF:

0.00308

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00248

GnomAD4 exome

AF:

0.00250

AC:

3509

AN:

1401382

Hom.:

Cov.:

AF XY:

0.00244

AC XY:

1690

AN XY:

692224

show subpopulations

Gnomad4 AFR exome

AF:

0.000315

Gnomad4 AMR exome

AF:

0.000881

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.000111

Gnomad4 SAS exome

AF:

0.00162

Gnomad4 FIN exome

AF:

0.00395

Gnomad4 NFE exome

AF:

0.00278

Gnomad4 OTH exome

AF:

0.00234

GnomAD4 genome

AF:

0.00192

AC:

292

AN:

152286

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00433

Gnomad4 NFE

AF:

0.00300

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00233

Hom.:

Bravo

AF:

0.00147

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000248

AC:

ESP6500EA

AF:

0.00146

AC:

ExAC

AF:

0.000963

AC:

110

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2016	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	- -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNAAF3: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2016	- -

DNAAF3-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0011

.;T;.;.

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.71

T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

.;L;.;.

MutationTaster

Benign

0.94

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.4

N;.;.;N

REVEL

Benign

0.13

Sift

Benign

0.23

T;.;.;T

Sift4G

Benign

0.34

T;T;T;T

Polyphen

0.99

.;D;.;.

Vest4

0.37

MVP

0.32

MPC

0.63

ClinPred

0.023

GERP RS

4.2

Varity_R

0.12

gMVP

0.69

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