NM_001256715.2:c.666T>C

Variant names:

• chr19-55161416-A-G
• rs7260320
• NM_001256715.2:c.666T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001256715.2(DNAAF3):​c.666T>C​(p.Ala222Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 750,756 control chromosomes in the GnomAD database, including 25,479 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (5891 hom., cov: 23)
  • Exomes 𝑓: 0.35 (19588 hom.)
• Consequence: DNAAF3 NM_001256715.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.00300

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 19-55161416-A-G is Benign according to our data. Variant chr19-55161416-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55161416-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.666T>C	p.Ala222Ala	splice_region_variant, synonymous_variant	Exon 7 of 12	ENST00000524407.7	NP_001243644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.666T>C	p.Ala222Ala	splice_region_variant, synonymous_variant	Exon 7 of 12	1	NM_001256715.2	ENSP00000432046.3

Frequencies

GnomAD3 genomes AF: 0.270 AC: 34601 AN: 128230 Hom.: 5876 Cov.: 23

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.324

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.271

GnomAD3 exomes AF: 0.184 AC: 33237 AN: 180944 Hom.: 3722 AF XY: 0.181 AC XY: 18128 AN XY: 100428

Gnomad AFR exome AF: 0.514

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.292

Gnomad EAS exome AF: 0.0935

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.105

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.349 AC: 217470 AN: 622406 Hom.: 19588 Cov.: 23 AF XY: 0.333 AC XY: 107367 AN XY: 322002

Gnomad4 AFR exome AF: 0.624

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.413

Gnomad4 EAS exome AF: 0.164

Gnomad4 SAS exome AF: 0.187

Gnomad4 FIN exome AF: 0.165

Gnomad4 NFE exome AF: 0.379

Gnomad4 OTH exome AF: 0.379

GnomAD4 genome AF: 0.270 AC: 34661 AN: 128350 Hom.: 5891 Cov.: 23 AF XY: 0.265 AC XY: 16285 AN XY: 61544

Gnomad4 AFR AF: 0.511

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.278

Gnomad4 EAS AF: 0.116

Gnomad4 SAS AF: 0.180

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.273

Alfa AF: 0.201 Hom.: 1655

Bravo AF: 0.259

Asia WGS AF: 0.162 AC: 563 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dilated Cardiomyopathy, Recessive Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial restrictive cardiomyopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.8
DANN	Benign	0.63

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: rs7260320; hg19: chr19-55672784; COSMIC: COSV61275049; COSMIC: COSV61275049;