rs78853309

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001369.3(DNAH5):c.7502G>C(p.Arg2501Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000762 in 1,548,374 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R2501R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000074 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 7.83

Variant links:

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.835

PP5

Variant 5-13810166-C-G is Pathogenic according to our data. Variant chr5-13810166-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179699.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.7502G>C	p.Arg2501Pro	missense_variant	45/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.7502G>C	p.Arg2501Pro	missense_variant	45/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.7457G>C	p.Arg2486Pro	missense_variant	45/79			A1
DNAH5	ENST00000512443.1 linkuse as main transcript	n.358G>C		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000206

AC:

AN:

145432

Hom.:

AF XY:

0.000204

AC XY:

AN XY:

78334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00353

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000187

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000745

AC:

104

AN:

1396162

Hom.:

Cov.:

AF XY:

0.0000726

AC XY:

AN XY:

688358

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00319

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.000208

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000941

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00403

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000339

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000700

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:3Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 05, 2023	The p.R2501P variant (also known as c.7502G>C), located in coding exon 45 of the DNAH5 gene, results from a G to C substitution at nucleotide position 7502. The arginine at codon 2501 is replaced by proline, an amino acid with dissimilar properties. This variant has been detected in multiple unrelated individuals with clinical features of primary ciliary dyskenesia who were homozygous or had one or two additional DNAH5 alterations (Hornef N et al. Am J Respir Crit Care Med, 2006 Jul;174:120-6; Failly M et al. J Med Genet, 2009 Apr;46:281-6; Davis SD et al. Am J Respir Crit Care Med, 2019 01;199:190-198; Fedick AM et al. Mol Genet Genomic Med, 2015 Mar;3:137-42; Bieder A et al. BMC Med Genet, 2020 05;21:87; Ambry internal data). This amino acid position is highly 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 2501 of the DNAH5 protein (p.Arg2501Pro). This variant is present in population databases (rs78853309, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 16627867, 19357118, 25802884, 30067075, 32357925; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This missense change has been observed to be homozygous or hemizygous in an individual who did not have the expected clinical features for that genetic result (Invitae). ClinVar contains an entry for this variant (Variation ID: 179699). 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 DNAH5 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 3

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 29, 2023	This DNAH5 missense variant along with another DNAH5 variant occurring in trans has been identified in two siblings affected with primay ciliary dyskinesia. The variant has also been reported in other unrelated individuals with primary ciliary dyskinesia. The variant (rs78853309) is rare (<0.1%) in a large population dataset (gnomAD v2.1.1: 31/176772 total alleles; 0.018%; no homozygotes) and has been reported in ClinVar6 (Variation ID: 179699). Two bioinformatic tools queried predict that this substitution would be damaging, and the arginine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.7502G>C; p.Arg2501Pro in DNAH5 to be uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 21, 2016	The DNAH5 c.7502G>C (p.Arg2501Pro) variant is a missense variant that has been reported in a total of three individuals with primary ciliary dyskinesia, two of whom were sibling. In the siblings, the variant was found in trans with consensus splice-site variant, while in the third individual, it was in a compound heterozygous state with a missense variant (Hornef et al. 2006; Fedick et al. 2015). In addition, Failly et al. (2009) reported the p.Arg2501Pro variant in a patient who also carried two other missense variants, with phase unknown. The p.Arg2501Pro variant was absent from 70 controls but is reported at a frequency of 0.00128 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg2501Pro variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 22, 2019

proposed classification - variant undergoing re-assessment, contact laboratory -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 13, 2022

Observed in multiple patients with primary ciliary diskinesia in published literature; patients harbored other variants in the DNAH5 gene but phase for most cases is not known (Hornef et al., 2006; Failly et al., 2009; Fedick et al., 2015; Bieder et al., 2020); 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: 19357118, 32357925, 25802884, 30067075, 16627867) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.16

Cadd

Uncertain

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.84

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.5

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0010

Polyphen

1.0

Vest4

0.98

MutPred

0.88

Loss of MoRF binding (P = 0.021);

MVP

0.83

MPC

0.31

ClinPred

0.87

GERP RS

5.4

Varity_R

0.90

gMVP

0.97

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.

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