rs2288021

Variant names:

• chr16-84176209-C-G
• rs2288021
• NM_178452.6:c.1975C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_178452.6(DNAAF1):​c.1975C>G​(p.Leu659Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.203 in 1,613,716 control chromosomes in the GnomAD database, including 34,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 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. L659P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.16 (2577 hom., cov: 33)
  • Exomes 𝑓: 0.21 (32338 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.430
• Publications: 18 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 -16 ACMG points.

• BP6: Variant 16-84176209-C-G is Benign according to our data. Variant chr16-84176209-C-G is described in ClinVar as Benign. ClinVar VariationId is 163088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 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.1975C>G	p.Leu659Val	missense	Exon 11 of 12	NP_848547.4
	DNAAF1	NM_001318756.1		c.1267C>G	p.Leu423Val	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.1975C>G	p.Leu659Val	missense	Exon 11 of 12	ENSP00000367815.5
	DNAAF1	ENST00000569735.1	TSL:2	c.277C>G	p.Leu93Val	missense	Exon 1 of 3	ENSP00000454960.1
	DNAAF1	ENST00000564928.1	TSL:2	c.67C>G	p.Leu23Val	missense	Exon 1 of 2	ENSP00000457899.1

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24898 AN: 152118 Hom.: 2576 Cov.: 33

Gnomad AFR AF: 0.0412

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.224

Gnomad EAS AF: 0.112

Gnomad SAS AF: 0.209

Gnomad FIN AF: 0.202

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.186

GnomAD2 exomes AF: 0.199 AC: 50022 AN: 250950 AF XY: 0.202

Gnomad AFR exome AF: 0.0375

Gnomad AMR exome AF: 0.220

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.207

GnomAD4 exome AF: 0.207 AC: 302398 AN: 1461480 Hom.: 32338 Cov.: 70 AF XY: 0.208 AC XY: 150975 AN XY: 727048

African (AFR) AF: 0.0357 AC: 1194 AN: 33480

American (AMR) AF: 0.217 AC: 9719 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 5743 AN: 26136

East Asian (EAS) AF: 0.0975 AC: 3870 AN: 39700

South Asian (SAS) AF: 0.214 AC: 18422 AN: 86256

European-Finnish (FIN) AF: 0.211 AC: 11212 AN: 53078

Middle Eastern (MID) AF: 0.279 AC: 1609 AN: 5768

European-Non Finnish (NFE) AF: 0.214 AC: 238319 AN: 1111974

Other (OTH) AF: 0.204 AC: 12310 AN: 60388

GnomAD4 genome AF: 0.164 AC: 24891 AN: 152236 Hom.: 2577 Cov.: 33 AF XY: 0.162 AC XY: 12030 AN XY: 74422

African (AFR) AF: 0.0411 AC: 1707 AN: 41562

American (AMR) AF: 0.203 AC: 3096 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 777 AN: 3470

East Asian (EAS) AF: 0.111 AC: 576 AN: 5170

South Asian (SAS) AF: 0.208 AC: 1006 AN: 4830

European-Finnish (FIN) AF: 0.202 AC: 2147 AN: 10606

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14958 AN: 67992

Other (OTH) AF: 0.186 AC: 394 AN: 2116

Alfa AF: 0.208 Hom.: 1129

Bravo AF: 0.159

TwinsUK AF: 0.207 AC: 768

ALSPAC AF: 0.201 AC: 775

ESP6500AA AF: 0.0436 AC: 192

ESP6500EA AF: 0.218 AC: 1878

ExAC AF: 0.197 AC: 23939

Asia WGS AF: 0.137 AC: 476 AN: 3478

EpiCase AF: 0.221

EpiControl AF: 0.221

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

Leu659Val in exon 11 of DNAAF1: This variant is not expected to have clinical si gnificance because it has been identified in 21.8% (1878/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs2288021).

Primary ciliary dyskinesia Benign:2

Nov 26, 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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 13 Benign:2

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	4.1
DANN	Benign	0.89
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.43
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.17	N
REVEL	Benign	0.032
Sift	Uncertain	0.022	D
Sift4G	Benign	0.093	T
Polyphen		0.013	B
Vest4		0.020
MPC		0.020
ClinPred		0.0023	T
GERP RS		0.29
PromoterAI		0.039	Neutral
Varity_R		0.049
gMVP		0.059
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.32		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2288021; hg19: chr16-84209815; COSMIC: COSV58987654; COSMIC: COSV58987654;