rs3734111

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369.3(DNAH5):c.13359A>G(p.Thr4453Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,605,764 control chromosomes in the GnomAD database, including 226,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18362 hom., cov: 30)

Exomes 𝑓: 0.53 ( 207948 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -5.33

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 5-13701416-T-C is Benign according to our data. Variant chr5-13701416-T-C is described in ClinVar as Benign. ClinVar VariationId is 178740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.13359A>G	p.Thr4453Thr	synonymous_variant	Exon 77 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH5	ENST00000265104.5 link	c.13359A>G	p.Thr4453Thr	synonymous_variant	Exon 77 of 79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 link	c.13314A>G	p.Thr4438Thr	synonymous_variant	Exon 77 of 79			ENSP00000505288.1	A0A7P0Z455
DNAH5	ENST00000683611.1 link	n.692A>G		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73509

AN:

151508

Hom.:

18346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.588

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.536

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.499

GnomAD2 exomes

AF:

0.503

AC:

126419

AN:

251126

AF XY:

0.503

show subpopulations

Gnomad AFR exome

AF:

0.371

Gnomad AMR exome

AF:

0.493

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.420

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.547

Gnomad OTH exome

AF:

0.518

GnomAD4 exome

AF:

0.531

AC:

772654

AN:

1454136

Hom.:

207948

Cov.:

AF XY:

0.529

AC XY:

382630

AN XY:

723818

show subpopulations

African (AFR)

AF:

0.360

AC:

12020

AN:

33362

American (AMR)

AF:

0.493

AC:

22031

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.526

AC:

13730

AN:

26100

East Asian (EAS)

AF:

0.388

AC:

15405

AN:

39662

South Asian (SAS)

AF:

0.443

AC:

38174

AN:

86076

European-Finnish (FIN)

AF:

0.528

AC:

28228

AN:

53416

Middle Eastern (MID)

AF:

0.497

AC:

2861

AN:

5758

European-Non Finnish (NFE)

AF:

0.551

AC:

609185

AN:

1104922

Other (OTH)

AF:

0.516

AC:

31020

AN:

60124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

17084

34168

51252

68336

85420

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17052

34104

51156

68208

85260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.485

AC:

73568

AN:

151628

Hom.:

18362

Cov.:

AF XY:

0.482

AC XY:

35701

AN XY:

74066

show subpopulations

African (AFR)

AF:

0.375

AC:

15479

AN:

41256

American (AMR)

AF:

0.499

AC:

7617

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.536

AC:

1858

AN:

3468

East Asian (EAS)

AF:

0.433

AC:

2234

AN:

5156

South Asian (SAS)

AF:

0.446

AC:

2146

AN:

4810

European-Finnish (FIN)

AF:

0.530

AC:

5540

AN:

10462

Middle Eastern (MID)

AF:

0.500

AC:

147

AN:

294

European-Non Finnish (NFE)

AF:

0.544

AC:

36957

AN:

67914

Other (OTH)

AF:

0.501

AC:

1055

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1871

3743

5614

7486

9357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

670

1340

2010

2680

3350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.524

Hom.:

61742

Bravo

AF:

0.479

Asia WGS

AF:

0.455

AC:

1584

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.552

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr4453Thr in exon 77 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 45.3% (3894/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3734111). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 11, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia 3

Benign:3

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 15, 2021

Pars Genome Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.0020

(source)

DANN

Benign

0.49

PhyloP100

-5.3

Mutation Taster

=81/19

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over