rs200291432

Positions:

• chr14-49634326-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The NM_018139.3(DNAAF2):​c.824C>T​(p.Ala275Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,611,652 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: DNAAF2 NM_018139.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.869

Genes affected

DNAAF2 (HGNC:20188): (dynein axonemal assembly factor 2) This gene encodes a highly conserved protein involved in the preassembly of dynein arm complexes which power cilia. These complexes are found in some cilia and are assembled in the cytoplasm prior to transport for cilia formation. Mutations in this gene have been associated with primary ciliary dyskinesia. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

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=0.0066659153).
• BP6: Variant 14-49634326-G-A is Benign according to our data. Variant chr14-49634326-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241283.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF2	NM_018139.3	c.824C>T	p.Ala275Val	missense_variant	1/3	ENST00000298292.13
DNAAF2	NM_001083908.2	c.824C>T	p.Ala275Val	missense_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF2	ENST00000298292.13	c.824C>T	p.Ala275Val	missense_variant	1/3	1	NM_018139.3	P2
DNAAF2	ENST00000406043.3	c.824C>T	p.Ala275Val	missense_variant	1/2	1		A2

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000261 AC: 63 AN: 241196 Hom.: 0 AF XY: 0.000271 AC XY: 36 AN XY: 132618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000557

Gnomad OTH exome AF: 0.000508

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1459318 Hom.: 1 Cov.: 88 AF XY: 0.000134 AC XY: 97 AN XY: 725964

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152334 Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000522

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000223

ExAC AF: 0.000216 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2015	The p.A275V variant (also known as c.824C>T), located in coding exon 1 of the DNAAF2 gene, results from a C to T substitution at nucleotide position 824. The alanine at codon 275 is replaced by valine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs200291432. This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6222 samples (12444 alleles) with coverage at this position. This amino acid position is not 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 variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	- -

Primary ciliary dyskinesia 10 Uncertain:1

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. -

DNAAF2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 14, 2020

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	0.095
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.94
DEOGEN2	Benign	0.0034	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.64	T;T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.0067	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.85	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.040
Sift	Benign	0.16	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.0010	B;B
Vest4		0.098
MutPred		0.45		Gain of catalytic residue at R272 (P = 0.1044);Gain of catalytic residue at R272 (P = 0.1044);
MVP		0.26
MPC		0.53
ClinPred		0.032	T
GERP RS		3.3
Varity_R		0.060
gMVP		0.40

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: rs200291432; hg19: chr14-50101044;