rs17845734

chr16-84170333-C-Tchr16-84170333-C-G

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.1505C>T(p.Pro502Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,613,566 control chromosomes in the GnomAD database, including 107,765 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P502P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (7769 hom., cov: 32)
  • Exomes 𝑓: 0.37 (99996 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.826

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=8.3488226E-4).
• BP6: Variant 16-84170333-C-T is Benign according to our data. Variant chr16-84170333-C-T is described in ClinVar as [Benign]. Clinvar id is 226575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84170333-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.368 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1505C>T	p.Pro502Leu	missense_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1505C>T	p.Pro502Leu	missense_variant	8/12	1	NM_178452.6	P1
DNAAF1	ENST00000563818.5	n.1182C>T		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5	n.1659C>T		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5	c.*60C>T		3_prime_UTR_variant, NMD_transcript_variant	9/11	2

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46589 AN: 151974 Hom.: 7761 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.329

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.318

GnomAD3 exomes AF: 0.344 AC: 85585 AN: 248686 Hom.: 15240 AF XY: 0.345 AC XY: 46532 AN XY: 134970

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.384

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.341

Gnomad SAS exome AF: 0.287

Gnomad FIN exome AF: 0.340

Gnomad NFE exome AF: 0.374

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.367 AC: 535884 AN: 1461474 Hom.: 99996 Cov.: 83 AF XY: 0.364 AC XY: 264345 AN XY: 727026

Gnomad4 AFR exome AF: 0.151

Gnomad4 AMR exome AF: 0.383

Gnomad4 ASJ exome AF: 0.359

Gnomad4 EAS exome AF: 0.331

Gnomad4 SAS exome AF: 0.286

Gnomad4 FIN exome AF: 0.339

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.348

GnomAD4 genome AF: 0.306 AC: 46609 AN: 152092 Hom.: 7769 Cov.: 32 AF XY: 0.306 AC XY: 22780 AN XY: 74340

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.366

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.330

Gnomad4 SAS AF: 0.288

Gnomad4 FIN AF: 0.339

Gnomad4 NFE AF: 0.372

Gnomad4 OTH AF: 0.315

Alfa AF: 0.363 Hom.: 16696

Bravo AF: 0.306

TwinsUK AF: 0.390 AC: 1445

ALSPAC AF: 0.383 AC: 1477

ESP6500AA AF: 0.160 AC: 700

ESP6500EA AF: 0.370 AC: 3176

ExAC AF: 0.338 AC: 40957

Asia WGS AF: 0.269 AC: 933 AN: 3478

EpiCase AF: 0.368

EpiControl AF: 0.374

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 06, 2015	p.Pro502Leu in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 37.5% (24168/64438) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs11644164). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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 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 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

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.29
Dann	Benign	0.23
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0041	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.00083	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.81	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.0060
Sift	Benign	0.53	T
Sift4G	Benign	0.40	T
Polyphen		0.0030	B
Vest4		0.049
MPC		0.020
ClinPred		0.00055	T
GERP RS		-0.20
Varity_R		0.019
gMVP		0.076

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: rs11644164; hg19: chr16-84203939; COSMIC: COSV57577083; COSMIC: COSV57577083;