16-84176258-G-C

Variant names:

• chr16-84176258-G-C
• rs2288023
• NM_178452.6:c.2024G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_178452.6(DNAAF1):​c.2024G>C​(p.Ser675Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.346 in 1,613,384 control chromosomes in the GnomAD database, including 100,057 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S675N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.29 (7330 hom., cov: 32)
  • Exomes 𝑓: 0.35 (92727 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0170
• Publications: 34 publications found

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]

DNAAF1 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 13

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.598732E-4).
• BP6: Variant 16-84176258-G-C is Benign according to our data. Variant chr16-84176258-G-C is described in ClinVar as Benign. ClinVar VariationId is 163090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_178452.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	NM_178452.6	MANE Select	c.2024G>C	p.Ser675Thr	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1316G>C	p.Ser439Thr	missense	Exon 7 of 8	NP_001305685.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAAF1	ENST00000378553.10	TSL:1 MANE Select	c.2024G>C	p.Ser675Thr	missense	Exon 11 of 12	ENSP00000367815.5
	DNAAF1	ENST00000569735.1	TSL:2	c.326G>C	p.Ser109Thr	missense	Exon 1 of 3	ENSP00000454960.1
	DNAAF1	ENST00000564928.1	TSL:2	c.116G>C	p.Ser39Thr	missense	Exon 1 of 2	ENSP00000457899.1

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43738 AN: 152012 Hom.: 7316 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.373

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.294

GnomAD2 exomes AF: 0.345 AC: 86651 AN: 250956 AF XY: 0.343

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.472

Gnomad ASJ exome AF: 0.294

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.363

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.336

GnomAD4 exome AF: 0.352 AC: 514354 AN: 1461254 Hom.: 92727 Cov.: 56 AF XY: 0.349 AC XY: 253641 AN XY: 726920

African (AFR) AF: 0.0965 AC: 3231 AN: 33480

American (AMR) AF: 0.464 AC: 20730 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 7767 AN: 26136

East Asian (EAS) AF: 0.379 AC: 15041 AN: 39700

South Asian (SAS) AF: 0.269 AC: 23188 AN: 86254

European-Finnish (FIN) AF: 0.362 AC: 19148 AN: 52858

Middle Eastern (MID) AF: 0.273 AC: 1575 AN: 5768

European-Non Finnish (NFE) AF: 0.363 AC: 403812 AN: 1111952

Other (OTH) AF: 0.329 AC: 19862 AN: 60384

GnomAD4 genome AF: 0.288 AC: 43759 AN: 152130 Hom.: 7330 Cov.: 32 AF XY: 0.292 AC XY: 21688 AN XY: 74342

African (AFR) AF: 0.108 AC: 4494 AN: 41556

American (AMR) AF: 0.390 AC: 5962 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1050 AN: 3468

East Asian (EAS) AF: 0.374 AC: 1927 AN: 5156

South Asian (SAS) AF: 0.271 AC: 1307 AN: 4822

European-Finnish (FIN) AF: 0.367 AC: 3873 AN: 10558

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.354 AC: 24051 AN: 67968

Other (OTH) AF: 0.291 AC: 613 AN: 2110

Alfa AF: 0.324 Hom.: 6289

Bravo AF: 0.287

TwinsUK AF: 0.375 AC: 1391

ALSPAC AF: 0.358 AC: 1380

ESP6500AA AF: 0.112 AC: 491

ESP6500EA AF: 0.356 AC: 3062

ExAC AF: 0.337 AC: 40850

Asia WGS AF: 0.281 AC: 975 AN: 3478

EpiCase AF: 0.343

EpiControl AF: 0.347

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser675Thr in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 35.6% (3062/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2288023).

Primary ciliary dyskinesia Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 10, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 13 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.1
DANN	Benign	0.83
DEOGEN2	Benign	0.0061	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.00096	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.017
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.049
Sift	Benign	0.45	T
Sift4G	Benign	0.15	T
Polyphen		0.021	B
Vest4		0.032
MPC		0.020
ClinPred		0.0032	T
GERP RS		-1.7
PromoterAI		0.0033	Neutral
Varity_R		0.093
gMVP		0.060
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2288023; hg19: chr16-84209864; COSMIC: COSV58984742; COSMIC: COSV58984742;