rs149778130

chr7-754772-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_017802.4(DNAAF5):c.1208G>A(p.Arg403Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000531 in 1,612,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R403W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08628926).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000394 (60/152298) while in subpopulation NFE AF= 0.000706 (48/68032). AF 95% confidence interval is 0.000547. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. 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/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1208G>A	p.Arg403Gln	missense_variant	5/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1208G>A	p.Arg403Gln	missense_variant	5/12
DNAAF5	NR_075098.2	n.1168G>A		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1208G>A	p.Arg403Gln	missense_variant	5/13	1	NM_017802.4	P1
DNAAF5	ENST00000440747.5	c.614G>A	p.Arg205Gln	missense_variant	5/13	2
DNAAF5	ENST00000437419.5	c.527G>A	p.Arg176Gln	missense_variant	4/5	5

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000705

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000285 AC: 71 AN: 248772 Hom.: 0 AF XY: 0.000304 AC XY: 41 AN XY: 134816

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000500

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000493

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000545 AC: 796 AN: 1460698 Hom.: 1 Cov.: 32 AF XY: 0.000539 AC XY: 392 AN XY: 726632

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.000659

Gnomad4 OTH exome AF: 0.000431

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74478

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000706

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000603 Hom.: 0

Bravo AF: 0.000378

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000288 AC: 35

EpiCase AF: 0.000600

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 02, 2023	The p.R403Q variant (also known as c.1208G>A), located in coding exon 5 of the DNAAF5 gene, results from a G to A substitution at nucleotide position 1208. The arginine at codon 403 is replaced by glutamine, an amino acid with highly similar properties. 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 alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 17, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 403 of the DNAAF5 protein (p.Arg403Gln). This variant is present in population databases (rs149778130, gnomAD 0.06%). 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: 454847). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAAF5 protein function with a negative predictive value of 80%. 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. -

Primary ciliary dyskinesia 18 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	20
Dann	Benign	0.94
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.64	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.20
Sift	Benign	0.62	T
Sift4G	Benign	0.35	T
Polyphen		0.60	P
Vest4		0.61
MVP		0.13
MPC		0.26
ClinPred		0.051	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.12

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: rs149778130; hg19: chr7-794409;