16-84154618-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting

The NM_178452.6(DNAAF1):c.394C>T(p.Arg132Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000446 in 1,614,154 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000047 ( 1 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.98

Variant links:

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]

DNAAF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000465 (68/1461882) while in subpopulation SAS AF= 0.000614 (53/86258). AF 95% confidence interval is 0.000482. There are 1 homozygotes in gnomad4_exome. There are 41 alleles in male gnomad4_exome subpopulation. Median coverage is 32. 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 rank	MANE	Protein	UniProt
DNAAF1	NM_178452.6 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 12	ENST00000378553.10	NP_848547.4	Q8NEP3-1A0A140VJN4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAAF1	ENST00000378553.10 link	c.394C>T	p.Arg132Cys	missense_variant	Exon 4 of 12	1	NM_178452.6	ENSP00000367815.5	Q8NEP3-1
DNAAF1	ENST00000567918.5 link	n.394C>T		non_coding_transcript_exon_variant	Exon 4 of 7	1		ENSP00000455154.1	H3BP51
DNAAF1	ENST00000563093.5 link	n.394C>T		non_coding_transcript_exon_variant	Exon 4 of 11	2		ENSP00000457373.1	Q8NEP3-3
DNAAF1	ENST00000570298.5 link	n.548C>T		non_coding_transcript_exon_variant	Exon 4 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251490

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000614

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Aug 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R132C variant (also known as c.394C>T), located in coding exon 4 of the DNAAF1 gene, results from a C to T substitution at nucleotide position 394. The arginine at codon 132 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Jul 25, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 132 of the DNAAF1 protein (p.Arg132Cys). This variant is present in population databases (rs538582505, gnomAD 0.06%). 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: 410281). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-0.75

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-6.9

REVEL

Uncertain

0.33

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.64

MVP

0.58

MPC

0.18

ClinPred

0.91

GERP RS

4.0

Varity_R

0.69

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over