rs17856705

Positions:

• chr16-84170006-A-G
• chr16-84170006-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178452.6(DNAAF1):​c.1178A>G​(p.Lys393Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,613,638 control chromosomes in the GnomAD database, including 158,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (11560 hom., cov: 33)
  • Exomes 𝑓: 0.44 (147044 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0210

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=1.163822E-4).
• BP6: Variant 16-84170006-A-G is Benign according to our data. Variant chr16-84170006-A-G is described in ClinVar as [Benign]. Clinvar id is 226572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170006-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.456 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1178A>G	p.Lys393Arg	missense_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1178A>G	p.Lys393Arg	missense_variant	8/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.377 AC: 57381 AN: 152070 Hom.: 11549 Cov.: 33

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.487

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.304

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.368

GnomAD3 exomes AF: 0.402 AC: 101023 AN: 251180 Hom.: 21103 AF XY: 0.402 AC XY: 54566 AN XY: 135792

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.411

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.342

Gnomad SAS exome AF: 0.306

Gnomad FIN exome AF: 0.441

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.408

GnomAD4 exome AF: 0.444 AC: 649027 AN: 1461448 Hom.: 147044 Cov.: 88 AF XY: 0.439 AC XY: 319329 AN XY: 727012

Gnomad4 AFR exome AF: 0.217

Gnomad4 AMR exome AF: 0.411

Gnomad4 ASJ exome AF: 0.383

Gnomad4 EAS exome AF: 0.332

Gnomad4 SAS exome AF: 0.306

Gnomad4 FIN exome AF: 0.443

Gnomad4 NFE exome AF: 0.471

Gnomad4 OTH exome AF: 0.414

GnomAD4 genome AF: 0.377 AC: 57415 AN: 152190 Hom.: 11560 Cov.: 33 AF XY: 0.375 AC XY: 27891 AN XY: 74402

Gnomad4 AFR AF: 0.227

Gnomad4 AMR AF: 0.405

Gnomad4 ASJ AF: 0.386

Gnomad4 EAS AF: 0.332

Gnomad4 SAS AF: 0.304

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.364

Alfa AF: 0.433 Hom.: 31504

Bravo AF: 0.369

TwinsUK AF: 0.476 AC: 1764

ALSPAC AF: 0.473 AC: 1822

ESP6500AA AF: 0.225 AC: 991

ESP6500EA AF: 0.457 AC: 3932

ExAC AF: 0.400 AC: 48528

Asia WGS AF: 0.286 AC: 994 AN: 3478

EpiCase AF: 0.442

EpiControl AF: 0.445

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	May 05, 2015	p.Lys393Arg in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance it has been identified in 45% (30157/66644) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs17856705). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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. -

Primary ciliary dyskinesia 13 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.1
DANN	Benign	0.67
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.00012	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.055
Sift	Benign	0.22	T
Sift4G	Benign	0.44	T
Polyphen		0.0010	B
Vest4		0.025
MPC		0.019
ClinPred		0.0016	T
GERP RS		0.13
Varity_R		0.025
gMVP		0.055

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: rs17856705; hg19: chr16-84203612; COSMIC: COSV57576724; COSMIC: COSV57576724;