rs140751779

chr16-84159745-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178452.6(DNAAF1):c.812G>A(p.Arg271Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.94

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046313524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.812G>A	p.Arg271Gln	missense_variant	6/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.812G>A	p.Arg271Gln	missense_variant	6/12	1	NM_178452.6	P1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000437 AC: 11 AN: 251444 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135902

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727138

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74442

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000595 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 24, 2021	The p.R271Q variant (also known as c.812G>A), located in coding exon 6 of the DNAAF1 gene, results from a G to A substitution at nucleotide position 812. The arginine at codon 271 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 31, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 271 of the DNAAF1 protein (p.Arg271Gln). This variant is present in population databases (rs140751779, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with DNAAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 525421). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.067
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.070
Sift	Benign	0.034	D
Sift4G	Benign	0.23	T
Polyphen		0.63	P
Vest4		0.39
MVP		0.31
MPC		0.038
ClinPred		0.14	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.44

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: rs140751779; hg19: chr16-84193350; COSMIC: COSV57577429;