rs755871359

chr7-770543-C-Gchr7-770543-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_017802.4(DNAAF5):c.1856C>G(p.Pro619Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P619L) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: DNAAF5 NM_017802.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAAF5	NM_017802.4	c.1856C>G	p.Pro619Arg	missense_variant	9/13	ENST00000297440.11
DNAAF5	XM_024446813.2	c.1856C>G	p.Pro619Arg	missense_variant	9/12
DNAAF5	NR_075098.2	n.1816C>G		non_coding_transcript_exon_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1856C>G	p.Pro619Arg	missense_variant	9/13	1	NM_017802.4	P1
DNAAF5	ENST00000403952.3	c.131C>G	p.Pro44Arg	missense_variant	2/6	1
DNAAF5	ENST00000440747.5	c.1262C>G	p.Pro421Arg	missense_variant	9/13	2
DNAAF5	ENST00000491496.1	n.141C>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74362

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2023

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. 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 expected to disrupt DNAAF5 protein function. ClinVar contains an entry for this variant (Variation ID: 1000540). This variant has not been reported in the literature in individuals affected with DNAAF5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 619 of the DNAAF5 protein (p.Pro619Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.074	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Uncertain	0.090	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.6	D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.43		Loss of loop (P = 0.0031);.;
MVP		0.41
MPC		0.67
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.59
gMVP		0.59

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: rs755871359; hg19: chr7-810180;