16-84154770-C-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_178452.6(DNAAF1):ā€‹c.546C>Gā€‹(p.Asn182Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,614,120 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0015 ( 0 hom., cov: 32)
Exomes š‘“: 0.0020 ( 6 hom. )

Consequence

DNAAF1
NM_178452.6 missense

Scores

2
8
9

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 1.98
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.09108555).
BP6
Variant 16-84154770-C-G is Benign according to our data. Variant chr16-84154770-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166997.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00148 (225/152298) while in subpopulation AMR AF= 0.00288 (44/15298). AF 95% confidence interval is 0.0022. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAAF1NM_178452.6 linkuse as main transcriptc.546C>G p.Asn182Lys missense_variant 4/12 ENST00000378553.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAAF1ENST00000378553.10 linkuse as main transcriptc.546C>G p.Asn182Lys missense_variant 4/121 NM_178452.6 P1Q8NEP3-1
DNAAF1ENST00000567918.5 linkuse as main transcriptc.546C>G p.Asn182Lys missense_variant, NMD_transcript_variant 4/71
DNAAF1ENST00000570298.5 linkuse as main transcriptn.700C>G non_coding_transcript_exon_variant 4/112
DNAAF1ENST00000563093.5 linkuse as main transcriptc.546C>G p.Asn182Lys missense_variant, NMD_transcript_variant 4/112 Q8NEP3-3

Frequencies

GnomAD3 genomes
AF:
0.00149
AC:
226
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000435
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00295
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000827
Gnomad FIN
AF:
0.000283
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00225
Gnomad OTH
AF:
0.00143
GnomAD3 exomes
AF:
0.00137
AC:
345
AN:
251476
Hom.:
0
AF XY:
0.00130
AC XY:
177
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.000492
Gnomad AMR exome
AF:
0.00197
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000294
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00220
Gnomad OTH exome
AF:
0.00130
GnomAD4 exome
AF:
0.00201
AC:
2935
AN:
1461822
Hom.:
6
Cov.:
32
AF XY:
0.00191
AC XY:
1390
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.000299
Gnomad4 AMR exome
AF:
0.00188
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000475
Gnomad4 FIN exome
AF:
0.000206
Gnomad4 NFE exome
AF:
0.00242
Gnomad4 OTH exome
AF:
0.00161
GnomAD4 genome
AF:
0.00148
AC:
225
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.00157
AC XY:
117
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000433
Gnomad4 AMR
AF:
0.00288
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000828
Gnomad4 FIN
AF:
0.000283
Gnomad4 NFE
AF:
0.00225
Gnomad4 OTH
AF:
0.00142
Alfa
AF:
0.00164
Hom.:
0
Bravo
AF:
0.00145
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.00130
AC:
5
ESP6500AA
AF:
0.000455
AC:
2
ESP6500EA
AF:
0.00326
AC:
28
ExAC
AF:
0.00124
AC:
151
EpiCase
AF:
0.00256
EpiControl
AF:
0.00190

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 17, 2014- -
Uncertain significance, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Uncertain significance, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Primary ciliary dyskinesia Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsSep 15, 2016This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingUNC Molecular Genetics Laboratory, University of North Carolina at Chapel HillJan 04, 2018- -
Primary ciliary dyskinesia 13 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.021
T
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.45
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.94
D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.091
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
2.0
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Pathogenic
-5.8
D
REVEL
Benign
0.19
Sift
Uncertain
0.016
D
Sift4G
Uncertain
0.0060
D
Polyphen
0.99
D
Vest4
0.91
MutPred
0.51
Gain of ubiquitination at N182 (P = 0.0289);
MVP
0.42
MPC
0.11
ClinPred
0.052
T
GERP RS
3.8
Varity_R
0.78
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs144018942; hg19: chr16-84188375; API