chr14-49633668-T-C

Position:

• chr14-49633668-T-C

Variant summary

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

The NM_018139.3(DNAAF2):​c.1482A>G​(p.Thr494Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.713 in 1,610,450 control chromosomes in the GnomAD database, including 423,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33831 hom., cov: 32)
  • Exomes 𝑓: 0.72 (389892 hom.)
• Consequence: DNAAF2 NM_018139.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -2.79

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-49633668-T-C is Benign according to our data. Variant chr14-49633668-T-C is described in ClinVar as [Benign]. Clinvar id is 95892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-49633668-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF2	NM_018139.3	c.1482A>G	p.Thr494Thr	synonymous_variant	1/3	ENST00000298292.13	NP_060609.2
DNAAF2	NM_001083908.2	c.1482A>G	p.Thr494Thr	synonymous_variant	1/2		NP_001077377.1
DNAAF2	NM_001378453.1	c.-390A>G		5_prime_UTR_variant	1/2		NP_001365382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF2	ENST00000298292.13	c.1482A>G	p.Thr494Thr	synonymous_variant	1/3	1	NM_018139.3	ENSP00000298292.8
DNAAF2	ENST00000406043.3	c.1482A>G	p.Thr494Thr	synonymous_variant	1/2	1		ENSP00000384862.3

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98327 AN: 151856 Hom.: 33816 Cov.: 32

Gnomad AFR AF: 0.483

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.661

Gnomad ASJ AF: 0.712

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.534

Gnomad FIN AF: 0.795

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.761

Gnomad OTH AF: 0.670

GnomAD3 exomes AF: 0.648 AC: 161163 AN: 248550 Hom.: 55997 AF XY: 0.652 AC XY: 87965 AN XY: 134842

Gnomad AFR exome AF: 0.471

Gnomad AMR exome AF: 0.601

Gnomad ASJ exome AF: 0.717

Gnomad EAS exome AF: 0.153

Gnomad SAS exome AF: 0.548

Gnomad FIN exome AF: 0.780

Gnomad NFE exome AF: 0.763

Gnomad OTH exome AF: 0.689

GnomAD4 exome AF: 0.720 AC: 1050070 AN: 1458478 Hom.: 389892 Cov.: 91 AF XY: 0.716 AC XY: 519182 AN XY: 725110

Gnomad4 AFR exome AF: 0.472

Gnomad4 AMR exome AF: 0.611

Gnomad4 ASJ exome AF: 0.720

Gnomad4 EAS exome AF: 0.122

Gnomad4 SAS exome AF: 0.547

Gnomad4 FIN exome AF: 0.775

Gnomad4 NFE exome AF: 0.767

Gnomad4 OTH exome AF: 0.679

GnomAD4 genome AF: 0.647 AC: 98395 AN: 151972 Hom.: 33831 Cov.: 32 AF XY: 0.645 AC XY: 47934 AN XY: 74294

Gnomad4 AFR AF: 0.483

Gnomad4 AMR AF: 0.661

Gnomad4 ASJ AF: 0.712

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.533

Gnomad4 FIN AF: 0.795

Gnomad4 NFE AF: 0.761

Gnomad4 OTH AF: 0.670

Alfa AF: 0.724 Hom.: 19885

Bravo AF: 0.629

Asia WGS AF: 0.392 AC: 1362 AN: 3478

EpiCase AF: 0.755

EpiControl AF: 0.765

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr494Thr in exon 1 of DNAAF2: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 48.9% (2153/4402) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2985687). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 10 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2014	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 provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.9
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs2985687; hg19: chr14-50100386; COSMIC: COSV53568251; COSMIC: COSV53568251;