rs150362958

Positions:

• chr19-55166408-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001256715.2(DNAAF3):​c.6C>T​(p.Thr2Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,794 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (13 hom., cov: 32)
  • Exomes 𝑓: 0.012 (118 hom.)
• Consequence: DNAAF3 NM_001256715.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.661

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 19-55166408-G-A is Benign according to our data. Variant chr19-55166408-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-55166408-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.661 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00817 (1244/152248) while in subpopulation NFE AF= 0.0145 (985/68020). AF 95% confidence interval is 0.0137. There are 13 homozygotes in gnomad4. There are 561 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF3	NM_001256715.2	c.6C>T	p.Thr2Thr	synonymous_variant	2/12	ENST00000524407.7	NP_001243644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF3	ENST00000524407.7	c.6C>T	p.Thr2Thr	synonymous_variant	2/12	1	NM_001256715.2	ENSP00000432046.3

Frequencies

GnomAD3 genomes AF: 0.00818 AC: 1244 AN: 152130 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00789 AC: 1959 AN: 248134 Hom.: 14 AF XY: 0.00786 AC XY: 1059 AN XY: 134756

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00386

Gnomad FIN exome AF: 0.00748

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.00893

GnomAD4 exome AF: 0.0122 AC: 17818 AN: 1461546 Hom.: 118 Cov.: 33 AF XY: 0.0120 AC XY: 8733 AN XY: 727052

Gnomad4 AFR exome AF: 0.00182

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00241

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00406

Gnomad4 FIN exome AF: 0.00839

Gnomad4 NFE exome AF: 0.0146

Gnomad4 OTH exome AF: 0.00881

GnomAD4 genome AF: 0.00817 AC: 1244 AN: 152248 Hom.: 13 Cov.: 32 AF XY: 0.00754 AC XY: 561 AN XY: 74442

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00565

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0112 Hom.: 8

Bravo AF: 0.00784

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	DNAAF3: BP4, BP7, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2020	- -

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 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 18, 2019	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

Nov 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.93

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: rs150362958; hg19: chr19-55677776;