rs145680314

Positions:

• chr16-84170182-C-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The ENST00000378553.10(DNAAF1):​c.1354C>A​(p.Pro452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,612,856 control chromosomes in the GnomAD database, including 1 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P452P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: DNAAF1 ENST00000378553.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: -0.0150

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013773799).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00081 (123/151836) while in subpopulation NFE AF= 0.00147 (100/67924). AF 95% confidence interval is 0.00124. There are 0 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF1	NM_178452.6	c.1354C>A	p.Pro452Thr	missense_variant	8/12	ENST00000378553.10	NP_848547.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF1	ENST00000378553.10	c.1354C>A	p.Pro452Thr	missense_variant	8/12	1	NM_178452.6	ENSP00000367815	P1
DNAAF1	ENST00000563818.5	n.1031C>A		non_coding_transcript_exon_variant	4/8	2
DNAAF1	ENST00000570298.5	n.1508C>A		non_coding_transcript_exon_variant	8/11	2
DNAAF1	ENST00000563093.5	c.1226-60C>A		intron_variant, NMD_transcript_variant		2		ENSP00000457373

Frequencies

GnomAD3 genomes AF: 0.000811 AC: 123 AN: 151722 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000761 AC: 191 AN: 250984 Hom.: 1 AF XY: 0.000854 AC XY: 116 AN XY: 135758

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00131

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.00137 AC: 1995 AN: 1461020 Hom.: 1 Cov.: 95 AF XY: 0.00135 AC XY: 978 AN XY: 726860

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.000506

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000810 AC: 123 AN: 151836 Hom.: 0 Cov.: 31 AF XY: 0.000714 AC XY: 53 AN XY: 74246

Gnomad4 AFR AF: 0.000339

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00135 Hom.: 0

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000807 AC: 98

EpiCase AF: 0.00164

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 08, 2019	The p.P452T variant (also known as c.1354C>A), located in coding exon 8 of the DNAAF1 gene, results from a C to A substitution at nucleotide position 1354. The proline at codon 452 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is well conserved on very 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 alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2022	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 452 of the DNAAF1 protein (p.Pro452Thr). This variant is present in population databases (rs145680314, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. 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: 216831). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Mar 02, 2021	- -

Primary ciliary dyskinesia 13 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 16, 2022	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2019

Variant classified as Uncertain Significance - Favor Benign. The p.Pro452Thr variant in DNAAF1 has not been previously reported in individuals with primary ciliary dyskinesia but has been reported in ClinVar (Variation ID 216831). It has also been identified in 0.13% (171/128786) of European chromosomes and in 0.15% (16/10346) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DNAAF1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	2.8
DANN	Benign	0.15
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.030
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.77	T
Polyphen		0.84	P
Vest4		0.22
MVP		0.24
MPC		0.074
ClinPred		0.020	T
GERP RS		0.54
Varity_R		0.090
gMVP		0.14

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: rs145680314; hg19: chr16-84203788; COSMIC: COSV100533753; COSMIC: COSV100533753;