rs140948493

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001369.3(DNAH5):c.11437C>T(p.Arg3813Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00144 in 1,613,698 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 4.49

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.31398964).

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.11437C>T	p.Arg3813Trp	missense_variant	Exon 66 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.11437C>T	p.Arg3813Trp	missense_variant	Exon 66 of 79	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 link	c.11392C>T	p.Arg3798Trp	missense_variant	Exon 66 of 79			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.00107

AC:

163

AN:

151792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000628

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00168

Gnomad OTH

AF:

0.00240

GnomAD3 exomes

AF:

0.00122

AC:

306

AN:

251212

Hom.:

AF XY:

0.00123

AC XY:

167

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00190

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00147

AC:

2156

AN:

1461788

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

1047

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000478

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00337

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000730

Gnomad4 FIN exome

AF:

0.000412

Gnomad4 NFE exome

AF:

0.00165

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00107

AC:

163

AN:

151910

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000628

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00168

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00143

Hom.:

Bravo

AF:

0.00123

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.00150

AC:

182

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Apr 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 34426522, 24498942) -

Dec 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3 -

Primary ciliary dyskinesia 3

Uncertain:2

Jun 19, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Pars Genome Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Uncertain:1Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R3813W variant (also known as c.11437C>T), located in coding exon 66 of the DNAH5 gene, results from a C to T substitution at nucleotide position 11437. The arginine at codon 3813 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was identified in an adult with a history of neonatal respiratory distress, otitis media, bronchiectasis, sinusitis and outer dynein arm defects on electron microscopy. This individual was also heterozygous for a nonsense alteration in DNAH5; however, the phase of these alterations was not provided (Kim RH et al. Ann Am Thorac Soc, 2014 Mar;11:351-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Uncertain:1

Feb 10, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg3813Trp variant in DNAH5 has been previously reported in 1 compound het erozygous child with primary ciliary dyskinesia (PCD) (Kim 2014). This variant h as also been identified in 0.24% (159/66720) of Non-Finnish European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSN P rs397515393). Computational prediction tools and conservation analysis sugges t that this variant may impact the protein, though this information is not predi ctive enough to determine pathogenicity. In summary, the clinical significance o f the p.Arg3813Trp variant is uncertain. -

DNAH5-related disorder

Uncertain:1

Apr 14, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DNAH5 c.11437C>T variant is predicted to result in the amino acid substitution p.Arg3813Trp. This variant was reported in the compound heterozygous state in an individual with primary ciliary dyskinesia (Table 1, Kim et al. 2014. PubMed ID: 24498942). This variant is reported in 0.34% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygous observation. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.076

MetaRNN

Benign

0.31

MetaSVM

Uncertain

0.61

MutationAssessor

Pathogenic

4.7

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.1

REVEL

Pathogenic

0.82

Sift

Uncertain

0.0030

Polyphen

1.0

Vest4

0.97

MVP

0.88

MPC

0.34

ClinPred

0.15

GERP RS

4.6

Varity_R

0.78

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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