rs149158199

chr16-84170131-G-Achr16-84170131-G-C

Variant summary

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

The NM_178452.6(DNAAF1):c.1303G>A(p.Asp435Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,590,246 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (65 hom., cov: 32)
  • Exomes 𝑓: 0.029 (691 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.03

Genes affected

DNAAF1 (HGNC:30539): (dynein axonemal assembly factor 1) The protein encoded by this gene is cilium-specific and is required for the stability of the ciliary architecture. It is involved in the regulation of microtubule-based cilia and actin-based brush border microvilli. Mutations in this gene are associated with primary ciliary dyskinesia-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034924448).
• BP6: Variant 16-84170131-G-A is Benign according to our data. Variant chr16-84170131-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170131-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0268 (4073/152082) while in subpopulation NFE AF= 0.0335 (2276/67958). AF 95% confidence interval is 0.0323. There are 65 homozygotes in gnomad4. There are 1867 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1303G>A	p.Asp435Asn	missense_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1303G>A	p.Asp435Asn	missense_variant	8/12	1	NM_178452.6	P1
DNAAF1	ENST00000563818.5	n.980G>A		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5	n.1457G>A		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5	c.1225+78G>A		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4067 AN: 151962 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0270

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0188

Gnomad MID AF: 0.0353

Gnomad NFE AF: 0.0335

Gnomad OTH AF: 0.0292

GnomAD3 exomes AF: 0.0251 AC: 6298 AN: 251304 Hom.: 93 AF XY: 0.0253 AC XY: 3432 AN XY: 135846

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.0222

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0128

Gnomad FIN exome AF: 0.0188

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0288 AC: 41467 AN: 1438164 Hom.: 691 Cov.: 97 AF XY: 0.0287 AC XY: 20530 AN XY: 714870

Gnomad4 AFR exome AF: 0.0193

Gnomad4 AMR exome AF: 0.0229

Gnomad4 ASJ exome AF: 0.0433

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0127

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0315

Gnomad4 OTH exome AF: 0.0303

GnomAD4 genome AF: 0.0268 AC: 4073 AN: 152082 Hom.: 65 Cov.: 32 AF XY: 0.0251 AC XY: 1867 AN XY: 74342

Gnomad4 AFR AF: 0.0221

Gnomad4 AMR AF: 0.0270

Gnomad4 ASJ AF: 0.0381

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0188

Gnomad4 NFE AF: 0.0335

Gnomad4 OTH AF: 0.0289

Alfa AF: 0.0299 Hom.: 77

Bravo AF: 0.0272

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0376 AC: 145

ESP6500AA AF: 0.0264 AC: 116

ESP6500EA AF: 0.0338 AC: 291

ExAC AF: 0.0252 AC: 3062

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0382

EpiControl AF: 0.0410

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Jan 29, 2016	p.Asp435Asn in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 3.3% (2200/66558) of European chro mosomes, including 39 homozygotes, by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs149158199). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 17, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Primary ciliary dyskinesia 13 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2020

This variant is associated with the following publications: (PMID: 31213628) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	8.5
Dann	Uncertain	1.0
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.071
Sift	Benign	0.038	D
Sift4G	Benign	0.42	T
Polyphen		0.61	P
Vest4		0.028
MPC		0.084
ClinPred		0.012	T
GERP RS		1.2
Varity_R		0.051
gMVP		0.082

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: rs149158199; hg19: chr16-84203737; COSMIC: COSV57577296; COSMIC: COSV57577296;