rs2288021

chr16-84176209-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.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. 13/21 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. 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:7
• Conservation: PhyloP100: -0.430

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=0.0032850504).
• BP6: Variant 16-84176209-C-G is Benign according to our data. Variant chr16-84176209-C-G is described in ClinVar as [Benign]. Clinvar id is 163088.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84176209-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1975C>G	p.Leu659Val	missense_variant	11/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1975C>G	p.Leu659Val	missense_variant	11/12	1	NM_178452.6	P1

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

GnomAD3 exomes AF: 0.199 AC: 50022 AN: 250950 Hom.: 5316 AF XY: 0.202 AC XY: 27400 AN XY: 135748

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 SAS exome AF: 0.212

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

Gnomad4 AFR exome AF: 0.0357

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.220

Gnomad4 EAS exome AF: 0.0975

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.211

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.204

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

Gnomad4 AFR AF: 0.0411

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.224

Gnomad4 EAS AF: 0.111

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.202

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.186

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
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	Nov 26, 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 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

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.17	N;N
REVEL	Benign	0.032
Sift	Uncertain	0.022	D;T
Sift4G	Benign	0.093	T;T
Polyphen		0.013	B;.
Vest4		0.020
MPC		0.020
ClinPred		0.0023	T
GERP RS		0.29
Varity_R		0.049
gMVP		0.059

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

Publications

LitVar

Other links and lift over

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