rs202084011

Positions:

chr19-55159561-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001256715.2(DNAAF3):c.1210G>A(p.Gly404Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000455 in 1,603,998 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

DNAAF3
NM_001256715.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.444

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04004672).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2 linkuse as main transcript	c.1210G>A	p.Gly404Arg	missense_variant	11/12	ENST00000524407.7	NP_001243644.1
DNAAF3-AS1	XR_007067344.1 linkuse as main transcript	n.137+116C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7 linkuse as main transcript	c.1210G>A	p.Gly404Arg	missense_variant	11/12	1	NM_001256715.2	ENSP00000432046	A2	Q8N9W5-1
DNAAF3-AS1	ENST00000591665.1 linkuse as main transcript	n.540C>T		non_coding_transcript_exon_variant	2/5	2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000625

AC:

AN:

240026

Hom.:

AF XY:

0.0000308

AC XY:

AN XY:

129814

show subpopulations

Gnomad AFR exome

AF:

0.000649

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000351

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000183

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.0000386

AC:

AN:

1451704

Hom.:

Cov.:

AF XY:

0.0000374

AC XY:

AN XY:

721250

show subpopulations

Gnomad4 AFR exome

AF:

0.000451

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000352

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000112

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000986

Hom.:

Bravo

AF:

0.000166

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 28, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 471 of the DNAAF3 protein (p.Gly471Arg). This variant is present in population databases (rs202084011, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAAF3-related conditions. ClinVar contains an entry for this variant (Variation ID: 454616). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.00077

.;T;.;.

Eigen

Benign

-0.46

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.040

T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

0.99

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

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.8

N;.;.;N

REVEL

Benign

0.10

Sift

Benign

0.39

T;.;.;T

Sift4G

Benign

0.52

T;T;T;T

Polyphen

0.63

.;P;.;.

Vest4

0.36

MutPred

0.41

.;Gain of methylation at G404 (P = 0.0301);.;.;

MVP

0.15

MPC

0.44

ClinPred

0.11

GERP RS

3.3

Varity_R

0.11

gMVP

0.52

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