rs772102523

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000297440.11(DNAAF5):​c.2375G>A​(p.Arg792Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

DNAAF5
ENST00000297440.11 missense

Scores

1
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.108
Variant links:
Genes affected
DNAAF5 (HGNC:26013): (dynein axonemal assembly factor 5) The protein encoded by this gene is essential for the preassembly or stability of axonemal dynein arms, and is found only in organisms with motile cilia and flagella. Mutations in this gene are associated with primary ciliary dyskinesia-18, a disorder characterized by abnormalities of motile cilia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.03825012).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAAF5NM_017802.4 linkuse as main transcriptc.2375G>A p.Arg792Gln missense_variant 12/13 ENST00000297440.11 NP_060272.3
DNAAF5XM_024446813.2 linkuse as main transcriptc.2239+4926G>A intron_variant XP_024302581.1
DNAAF5NR_075098.2 linkuse as main transcriptn.2335G>A non_coding_transcript_exon_variant 12/13

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAAF5ENST00000297440.11 linkuse as main transcriptc.2375G>A p.Arg792Gln missense_variant 12/131 NM_017802.4 ENSP00000297440 P1Q86Y56-1
DNAAF5ENST00000403952.3 linkuse as main transcriptc.650G>A p.Arg217Gln missense_variant 5/61 ENSP00000384884
DNAAF5ENST00000440747.5 linkuse as main transcriptc.1781G>A p.Arg594Gln missense_variant 12/132 ENSP00000403165
DNAAF5ENST00000461576.1 linkuse as main transcriptn.185G>A non_coding_transcript_exon_variant 1/22

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152230
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251358
Hom.:
0
AF XY:
0.0000368
AC XY:
5
AN XY:
135840
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:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000643
AC:
94
AN:
1461860
Hom.:
0
Cov.:
31
AF XY:
0.0000715
AC XY:
52
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000737
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152230
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 07, 2022The p.R792Q variant (also known as c.2375G>A), located in coding exon 12 of the DNAAF5 gene, results from a G to A substitution at nucleotide position 2375. The arginine at codon 792 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 21, 2022This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 792 of the DNAAF5 protein (p.Arg792Gln). This variant is present in population databases (rs772102523, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. ClinVar contains an entry for this variant (Variation ID: 410301). 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 tolerated. 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. -
DNAAF5-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesMay 06, 2024The DNAAF5 c.2375G>A variant is predicted to result in the amino acid substitution p.Arg792Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
2.8
DANN
Benign
0.91
DEOGEN2
Benign
0.031
T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.3
FATHMM_MKL
Benign
0.021
N
LIST_S2
Uncertain
0.86
D;D
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.038
T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.040
N;N
REVEL
Benign
0.020
Sift
Benign
0.67
T;T
Sift4G
Benign
0.60
T;T
Polyphen
0.22
B;B
Vest4
0.14
MutPred
0.37
Gain of catalytic residue at R792 (P = 0.3199);.;
MVP
0.040
MPC
0.19
ClinPred
0.027
T
GERP RS
-2.3
Varity_R
0.019
gMVP
0.080

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: rs772102523; hg19: chr7-819725; COSMIC: COSV52419122; COSMIC: COSV52419122; API