rs200365972

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PVS1_SupportingPM2BP6BS1

The NM_001256714.1(DNAAF3):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00023 in 1,613,088 control chromosomes in the GnomAD database, with no homozygous occurrence. 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‘“ 0.0012 ( 0 hom., cov: 32)
Exomes š‘“: 0.00013 ( 0 hom. )

Consequence

DNAAF3
NM_001256714.1 start_lost

Scores

3
1
11

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.310
Variant links:
Genes affected
DNAAF3 (HGNC:30492): (dynein axonemal assembly factor 3) The protein encoded by this gene is required for the assembly of axonemal inner and outer dynein arms and plays a role in assembling dynein complexes for transport into cilia. Defects in this gene are a cause of primary ciliary dyskinesia type 2 (CILD2). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
DNAAF3-AS1 (HGNC:55292): (DNAAF3 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 48 codons. Genomic position: 55166413. Lost 0.078 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 19-55166647-A-G is Benign according to our data. Variant chr19-55166647-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 416072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00123 (188/152322) while in subpopulation AFR AF= 0.00431 (179/41578). AF 95% confidence interval is 0.00379. There are 0 homozygotes in gnomad4. There are 91 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DNAAF3NM_001256715.2 linkc.-129T>C upstream_gene_variant ENST00000524407.7 NP_001243644.1 Q8N9W5-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DNAAF3ENST00000524407.7 linkc.-129T>C upstream_gene_variant 1 NM_001256715.2 ENSP00000432046.3 Q8N9W5-1

Frequencies

GnomAD3 genomes
AF:
0.00122
AC:
186
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00427
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000302
AC:
75
AN:
248354
Hom.:
0
AF XY:
0.000282
AC XY:
38
AN XY:
134826
show subpopulations
Gnomad AFR exome
AF:
0.00375
Gnomad AMR exome
AF:
0.000319
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000354
Gnomad OTH exome
AF:
0.000332
GnomAD4 exome
AF:
0.000125
AC:
183
AN:
1460766
Hom.:
0
Cov.:
32
AF XY:
0.000110
AC XY:
80
AN XY:
726670
show subpopulations
Gnomad4 AFR exome
AF:
0.00290
Gnomad4 AMR exome
AF:
0.000403
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.000348
GnomAD4 genome
AF:
0.00123
AC:
188
AN:
152322
Hom.:
0
Cov.:
32
AF XY:
0.00122
AC XY:
91
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.00431
Gnomad4 AMR
AF:
0.000457
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000223
Hom.:
0
Bravo
AF:
0.00130
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00352
AC:
14
ESP6500EA
AF:
0.000120
AC:
1
ExAC
AF:
0.000372
AC:
45
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:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:1
May 01, 2023
Mayo Clinic Laboratories, Mayo Clinic
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Primary ciliary dyskinesia Benign:2
Oct 13, 2017
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely 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. -

Jan 15, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
8.6
DANN
Benign
0.55
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.14
N
LIST_S2
Uncertain
0.90
D;D
M_CAP
Benign
0.0068
T
MetaRNN
Benign
0.0081
T;T
MetaSVM
Benign
-1.0
T
PROVEAN
Pathogenic
-5.0
D;N
REVEL
Benign
0.11
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
.;D
Vest4
0.20
MVP
0.048
ClinPred
0.058
T
GERP RS
-3.7
gMVP
0.33

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

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

Other links and lift over

dbSNP: rs200365972; hg19: chr19-55678015; COSMIC: COSV62830870; COSMIC: COSV62830870; API