rs114601492

chr19-55159283-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001256715.2(DNAAF3):c.1405G>A(p.Val469Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,614,078 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00078 (15 hom.)
• Consequence: DNAAF3 NM_001256715.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.11

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=0.002953142).
• BP6: Variant 19-55159283-C-T is Benign according to our data. Variant chr19-55159283-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 369295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55159283-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00807 (1230/152324) while in subpopulation AFR AF= 0.028 (1165/41564). AF 95% confidence interval is 0.0267. There are 19 homozygotes in gnomad4. There are 586 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF3	NM_001256715.2	c.1405G>A	p.Val469Met	missense_variant	12/12	ENST00000524407.7
DNAAF3-AS1	XR_007067344.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF3	ENST00000524407.7	c.1405G>A	p.Val469Met	missense_variant	12/12	1	NM_001256715.2	A2
DNAAF3-AS1	ENST00000591665.1	n.345C>T		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.00807 AC: 1228 AN: 152206 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

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: 0.0000294

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00212 AC: 529 AN: 249320 Hom.: 10 AF XY: 0.00166 AC XY: 225 AN XY: 135314

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000779 AC: 1138 AN: 1461754 Hom.: 15 Cov.: 31 AF XY: 0.000652 AC XY: 474 AN XY: 727200

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00807 AC: 1230 AN: 152324 Hom.: 19 Cov.: 33 AF XY: 0.00787 AC XY: 586 AN XY: 74492

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00617

Alfa AF: 0.00188 Hom.: 6

Bravo AF: 0.00905

ESP6500AA AF: 0.0250 AC: 99

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00258 AC: 312

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 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. -

Primary ciliary dyskinesia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 22, 2023

- -

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

- -

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Familial restrictive 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	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.61	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.51	N;.;.;N
REVEL	Benign	0.070
Sift	Benign	0.060	T;.;.;D
Sift4G	Uncertain	0.054	T;T;T;T
Polyphen		0.96	.;D;.;.
Vest4		0.12
MVP		0.13
MPC		0.67
ClinPred		0.027	T
GERP RS		-0.29
Varity_R		0.019
gMVP		0.27

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: rs114601492; hg19: chr19-55670651;