rs147811057

Positions:

• chr7-756782-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_017802.4(DNAAF5):​c.1258T>C​(p.Cys420Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000445 in 1,460,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: DNAAF5 NM_017802.4 missense, splice_region
• Scores: Splicing: ADA: 0.00005478
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 1.96

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 Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807
• PP5: Variant 7-756782-T-C is Pathogenic according to our data. Variant chr7-756782-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 454849.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAAF5	NM_017802.4	c.1258T>C	p.Cys420Arg	missense_variant, splice_region_variant	6/13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2	c.1258T>C	p.Cys420Arg	missense_variant, splice_region_variant	6/12		XP_024302581.1
DNAAF5	NR_075098.2	n.1218T>C		splice_region_variant, non_coding_transcript_exon_variant	6/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11	c.1258T>C	p.Cys420Arg	missense_variant, splice_region_variant	6/13	1	NM_017802.4	ENSP00000297440	P1
DNAAF5	ENST00000440747.5	c.664T>C	p.Cys222Arg	missense_variant, splice_region_variant	6/13	2		ENSP00000403165
DNAAF5	ENST00000437419.5	c.577T>C	p.Cys193Arg	missense_variant, splice_region_variant	5/5	5		ENSP00000410788

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 250998 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135780

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1460678 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 32 AN XY: 726498

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000755

Gnomad4 NFE exome AF: 0.0000468

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000703 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 02, 2017	The p.C420R variant (also known as c.1258T>C) is located in coding exon 6 of the DNAAF5 gene. The cysteine at codon 420 is replaced by arginine, an amino acid with highly dissimilar properties. This change occurs in the first base pair of coding exon 6. This variant was confirmed in trans with a gross deletion in DNAAF5 by our laboratory in an individual with clinical features consistent with primary ciliary dyskinesia. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2022	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 454849). This missense change has been observed in individual(s) with DNAAF5-related conditions (Invitae). This variant is present in population databases (rs147811057, gnomAD 0.01%). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 420 of the DNAAF5 protein (p.Cys420Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.97	D
Vest4		0.78
MVP		0.36
MPC		0.84
ClinPred		0.64	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.016
SpliceAI score (max)		0.020		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: rs147811057; hg19: chr7-796419;