rs144034147

Positions:

• chr16-84170033-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_178452.6(DNAAF1):​c.1205A>T​(p.Glu402Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000229 in 1,613,884 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: DNAAF1 NM_178452.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: -0.199

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023021698).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000237 (347/1461532) while in subpopulation MID AF= 0.00783 (43/5492). AF 95% confidence interval is 0.00597. There are 4 homozygotes in gnomad4_exome. There are 182 alleles in male gnomad4_exome subpopulation. Median coverage is 94. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF1	NM_178452.6	c.1205A>T	p.Glu402Val	missense_variant	8/12	ENST00000378553.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1205A>T	p.Glu402Val	missense_variant	8/12	1	NM_178452.6	P1
DNAAF1	ENST00000563818.5	n.882A>T		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5	n.1359A>T		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5	c.1205A>T	p.Glu402Val	missense_variant, NMD_transcript_variant	8/11	2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251290 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000237 AC: 347 AN: 1461532 Hom.: 4 Cov.: 94 AF XY: 0.000250 AC XY: 182 AN XY: 727082

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000237

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74508

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000134 Hom.: 0

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000491

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 13 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 06, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 26, 2015	The p.E402V variant (also known as c.1205A>T), located in coding exon 8 of the DNAAF1 gene, results from an A to T substitution at nucleotide position 1205. The glutamic acid at codon 402 is replaced by valine, an amino acid with dissimilar properties. This variant was previously reported in the SNPDatabase as rs144034147. Based on data from the 1000 Genomes Project, the T allele has an overall frequency of approximately 0.1% (2/2098) total alleles studied. The highest observed frequency was 0.59% (1/170) British alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (2/12998) total alleles studied and 0.02% (2/8598) European American alleles. This amino acid position is poorly conserved on limited sequence alignment. 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 variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 402 of the DNAAF1 protein (p.Glu402Val). This variant is present in population databases (rs144034147, gnomAD 0.02%). This missense change has been observed in individuals with clinical features of primary ciliary dyskinesia (Invitae). ClinVar contains an entry for this variant (Variation ID: 402597). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Gene associated with PCD and seminoma, no second allele -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.1
DANN	Benign	0.83
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.0040
Sift	Benign	0.23	T
Sift4G	Benign	0.11	T
Polyphen		0.025	B
Vest4		0.084
MVP		0.15
MPC		0.023
ClinPred		0.021	T
GERP RS		0.49
Varity_R		0.063
gMVP		0.23

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: rs144034147; hg19: chr16-84203639;