rs2365725

chr19-55161102-T-C

Variant summary

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

The NM_001256715.2(DNAAF3):c.875A>G(p.Glu292Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,543,812 control chromosomes in the GnomAD database, including 25,671 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (6211 hom., cov: 32)
  • Exomes 𝑓: 0.15 (19460 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.950

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.026724E-4).
• BP6: Variant 19-55161102-T-C is Benign according to our data. Variant chr19-55161102-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55161102-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.875A>G	p.Glu292Gly	missense_variant	8/12	ENST00000524407.7
DNAAF3-AS1	XR_007067344.1	n.194T>C		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.875A>G	p.Glu292Gly	missense_variant	8/12	1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.1024T>C		non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36390 AN: 151792 Hom.: 6195 Cov.: 32

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.258

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.0990

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.149

Gnomad OTH AF: 0.240

GnomAD3 exomes AF: 0.159 AC: 23233 AN: 146054 Hom.: 2449 AF XY: 0.157 AC XY: 12384 AN XY: 78706

Gnomad AFR exome AF: 0.491

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.251

Gnomad EAS exome AF: 0.0796

Gnomad SAS exome AF: 0.137

Gnomad FIN exome AF: 0.0948

Gnomad NFE exome AF: 0.156

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.155 AC: 215579 AN: 1391902 Hom.: 19460 Cov.: 40 AF XY: 0.154 AC XY: 105741 AN XY: 686722

Gnomad4 AFR exome AF: 0.498

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.0513

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.148

Gnomad4 OTH exome AF: 0.182

GnomAD4 genome AF: 0.240 AC: 36452 AN: 151910 Hom.: 6211 Cov.: 32 AF XY: 0.231 AC XY: 17183 AN XY: 74252

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.165

Gnomad4 ASJ AF: 0.258

Gnomad4 EAS AF: 0.0828

Gnomad4 SAS AF: 0.136

Gnomad4 FIN AF: 0.0990

Gnomad4 NFE AF: 0.149

Gnomad4 OTH AF: 0.242

Alfa AF: 0.173 Hom.: 5389

Bravo AF: 0.259

TwinsUK AF: 0.156 AC: 580

ALSPAC AF: 0.140 AC: 541

ESP6500AA AF: 0.367 AC: 1334

ESP6500EA AF: 0.123 AC: 922

ExAC AF: 0.0889 AC: 6989

Asia WGS AF: 0.164 AC: 569 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Primary ciliary dyskinesia 2 Benign:2

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	-	- -

Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated Cardiomyopathy, Recessive Benign:1

Likely 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

Jul 09, 2018

- -

Familial restrictive cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hypertrophic cardiomyopathy Benign:1

Likely 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	0.088
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Uncertain	1.0
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.53	T;T;T;T
MetaRNN	Benign	0.00030	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-4.6	D;.;.;D
REVEL	Benign	0.088
Sift	Uncertain	0.013	D;.;.;D
Sift4G	Uncertain	0.031	D;D;D;D
Polyphen		0.76	.;P;.;.
Vest4		0.072
MPC		0.52
ClinPred		0.027	T
GERP RS		3.2
Varity_R		0.10
gMVP		0.56

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: rs2365725; hg19: chr19-55672470; COSMIC: COSV61275481; COSMIC: COSV61275481;