rs35504640

chr16-84169905-G-Achr16-84169905-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_178452.6(DNAAF1):c.1077G>A(p.Ala359=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0291 in 1,614,104 control chromosomes in the GnomAD database, including 905 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (125 hom., cov: 33)
  • Exomes 𝑓: 0.029 (780 hom.)
• Consequence: DNAAF1 NM_178452.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.72

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 16-84169905-G-A is Benign according to our data. Variant chr16-84169905-G-A is described in ClinVar as [Benign]. Clinvar id is 226570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-84169905-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.72 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1077G>A	p.Ala359=	synonymous_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1077G>A	p.Ala359=	synonymous_variant	8/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.0340 AC: 5174 AN: 152218 Hom.: 126 Cov.: 33

Gnomad AFR AF: 0.0571

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0496

Gnomad FIN AF: 0.00442

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0285 AC: 7173 AN: 251426 Hom.: 177 AF XY: 0.0301 AC XY: 4097 AN XY: 135918

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0343

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0560

Gnomad FIN exome AF: 0.00545

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0401

GnomAD4 exome AF: 0.0286 AC: 41855 AN: 1461768 Hom.: 780 Cov.: 32 AF XY: 0.0295 AC XY: 21428 AN XY: 727178

Gnomad4 AFR exome AF: 0.0572

Gnomad4 AMR exome AF: 0.0201

Gnomad4 ASJ exome AF: 0.0360

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0538

Gnomad4 FIN exome AF: 0.00623

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0332

GnomAD4 genome AF: 0.0340 AC: 5175 AN: 152336 Hom.: 125 Cov.: 33 AF XY: 0.0333 AC XY: 2478 AN XY: 74490

Gnomad4 AFR AF: 0.0573

Gnomad4 AMR AF: 0.0279

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0487

Gnomad4 FIN AF: 0.00442

Gnomad4 NFE AF: 0.0270

Gnomad4 OTH AF: 0.0364

Alfa AF: 0.0267 Hom.: 42

Bravo AF: 0.0361

Asia WGS AF: 0.0240 AC: 84 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0331

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	May 05, 2015	p.Ala359Ala in exon 8 of DNAAF1: This variant is not expected to have clinical s ignificance because it has been identified in 2.7% (1807/66732) of European chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs35504640). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 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. -

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

Mar 25, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.2
Dann	Benign	0.37

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: rs35504640; hg19: chr16-84203511;