rs2288023

Positions:

• chr16-84176258-G-C
• chr16-84176258-G-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.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. 14/20 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:6
• Conservation: PhyloP100: -0.0170

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=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 id is 163090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84176258-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.2024G>C	p.Ser675Thr	missense_variant	11/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.2024G>C	p.Ser675Thr	missense_variant	11/12	1	NM_178452.6	P1

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

GnomAD3 exomes AF: 0.345 AC: 86651 AN: 250956 Hom.: 16032 AF XY: 0.343 AC XY: 46548 AN XY: 135758

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 SAS exome AF: 0.270

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

Gnomad4 AFR exome AF: 0.0965

Gnomad4 AMR exome AF: 0.464

Gnomad4 ASJ exome AF: 0.297

Gnomad4 EAS exome AF: 0.379

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.363

Gnomad4 OTH exome AF: 0.329

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

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.303

Gnomad4 EAS AF: 0.374

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.367

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.291

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Feb 21, 2013	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

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:1

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	0.086
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;T
MetaRNN	Benign	0.00096	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.049
Sift	Benign	0.45	T;T
Sift4G	Benign	0.15	T;T
Polyphen		0.021	B;.
Vest4		0.032
MPC		0.020
ClinPred		0.0032	T
GERP RS		-1.7
Varity_R		0.093
gMVP		0.060

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