chr7-761781-G-T

Position:

chr7-761781-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_017802.4(DNAAF5):c.1499G>T(p.Cys500Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000198 in 1,608,784 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

DNAAF5
NM_017802.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6U:1

Conservation

PhyloP100: 7.15

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]

DNAAF5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 7-761781-G-T is Pathogenic according to our data. Variant chr7-761781-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 410302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
DNAAF5	NM_017802.4 linkuse as main transcript	c.1499G>T	p.Cys500Phe	missense_variant	7/13	ENST00000297440.11	NP_060272.3
DNAAF5	XM_024446813.2 linkuse as main transcript	c.1499G>T	p.Cys500Phe	missense_variant	7/12		XP_024302581.1
DNAAF5	NR_075098.2 linkuse as main transcript	n.1459G>T		non_coding_transcript_exon_variant	7/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAAF5	ENST00000297440.11 linkuse as main transcript	c.1499G>T	p.Cys500Phe	missense_variant	7/13	1	NM_017802.4	ENSP00000297440	P1	Q86Y56-1
DNAAF5	ENST00000440747.5 linkuse as main transcript	c.905G>T	p.Cys302Phe	missense_variant	7/13	2		ENSP00000403165

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000100

AC:

AN:

239640

Hom.:

AF XY:

0.0000847

AC XY:

AN XY:

129812

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000207

AC:

301

AN:

1456540

Hom.:

Cov.:

AF XY:

0.000192

AC XY:

139

AN XY:

724026

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

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:

0.00

Gnomad4 NFE exome

AF:

0.000267

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000118

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74390

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000907

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 18

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 14, 2023	This DNAAF5 missense variant has been reported in the compound heterozygous and homozygous states in individuals with primary ciliary dyskinesia, and has also been shown to segregate with disease . It (rs144405450) is rare (<0.1%) in a large population dataset (gnomAD v4.0.0: 319/1608784 total alleles; 0.02%; no homozygotes), and has been reported in ClinVar (Variation ID 410302). Two bioinformatic tools queried predict that this substitution would be damaging, and the cysteine residue at this position is evolutionarily conserved across all of the species assessed. Additionally, functional studies support the prediction that this variant is deleterious, although these findings are insufficient to make a conclusion at this time. We consider c.1499G>T in DNAAF5 to be likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 12, 2019	- -
Uncertain significance, flagged submission	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Jul 04, 2023	The DNAAF5 c.1499G>T variant is classified as Likely Pathogenic (PM2, PM3, PP1_Supporting, PS3_Supporting) The DNAAF5 c.1499G>T variant is a single nucleotide change in exon 7/13 of the DNAAF5 gene, which is predicted to change the amino acid cysteine at position 500 in the protein to phenylalanine. The variant is rare in population databases (gnomAD allele frequency = 0.011%; 18 het and 0 hom in 152,244 sequenced alleles) (PM2). The variant has been reported in dbSNP (rs144405450), the HGMD database as disease causing (CM184879) and with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 410302). It has been reported in the literature in a pair of siblings with PCD who also harboured a DNAAF5 frameshift variant, however the phase was not specified (PMID: 29363216). The variant has been reported in the homozygous state in two siblings affected by PCD (PMID: 29358401) (PM3, PP1_Supporting). The homozygous siblings both showed mild sinusitis, mild otitis media and absent inner/outer dynein arms on TEM. The proband also presented with situs inversus. Functional studies by the authors using patients' nasal epithelial cells showed a detrimental effect on protein function (PS3_Supporting). -

Primary ciliary dyskinesia

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 500 of the DNAAF5 protein (p.Cys500Phe). This variant is present in population databases (rs144405450, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 29358401, 29363216). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 410302). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on DNAAF5 function (PMID: 29358401). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 2019	The p.C500F variant (also known as c.1499G>T), located in coding exon 7 of the DNAAF5 gene, results from a G to T substitution at nucleotide position 1499. The cysteine at codon 500 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant has been described homozygous in a pair of siblings with primary ciliary dyskinesia as well as two siblings in a second family in conjunction with a frameshift mutation, but phase was not specified in the latter (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228; Paff T et al. Hum. Mutat., 2018 05;39:653-665). In addition, functional studies of the p.C500F homozygous patients' nasal epithelial cells showed increased HEATR2-SPAG1 protein aggregates as well as misfolded proteins involved in the preassembly complex, which the authors suggest could cause instability; however; information on the sequencing of other involved genes were not available (Horani A et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:E1221-E1228). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2023

Identified with a second variant (phase unknown) in individuals with primary ciliary dyskinesia referred for genetic testing at GeneDx and in published literature (Paff et al., 2018); Published functional studies in mice demonstrate a damaging effect which results in cilia defects, reduced cilia motility, and developmental abnormalities (Horani et al., 2023); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29358401, 36712068, 29363216) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Benign

0.071

MetaRNN

Pathogenic

0.91

MetaSVM

Benign

-0.60

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.5

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MVP

0.36

MPC

0.61

ClinPred

0.97

GERP RS

5.4

Varity_R

0.90

gMVP

0.66

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over