NM_001369.3:c.12658A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369.3(DNAH5):c.12658A>G(p.Thr4220Ala) variant causes a missense change. The variant allele was found at a frequency of 0.107 in 1,613,678 control chromosomes in the GnomAD database, including 14,021 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4220T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.098 ( 1256 hom., cov: 32)

Exomes 𝑓: 0.11 ( 12765 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.14

Publications

35 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024172068).

BP6

Variant 5-13717362-T-C is Benign according to our data. Variant chr5-13717362-T-C is described in ClinVar as Benign. ClinVar VariationId is 178741.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.354 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.12658A>G	p.Thr4220Ala	missense_variant	Exon 73 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.12658A>G	p.Thr4220Ala	missense_variant	Exon 73 of 79	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 link	c.12613A>G	p.Thr4205Ala	missense_variant	Exon 73 of 79			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.0984

AC:

14957

AN:

152060

Hom.:

1254

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0253

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.209

Gnomad ASJ

AF:

0.0692

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0869

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.149

AC:

37351

AN:

250530

AF XY:

0.144

show subpopulations

Gnomad AFR exome

AF:

0.0209

Gnomad AMR exome

AF:

0.307

Gnomad ASJ exome

AF:

0.0692

Gnomad EAS exome

AF:

0.387

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.0834

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.108

AC:

158236

AN:

1461500

Hom.:

12765

Cov.:

AF XY:

0.109

AC XY:

79560

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.0186

AC:

622

AN:

33478

American (AMR)

AF:

0.300

AC:

13372

AN:

44642

Ashkenazi Jewish (ASJ)

AF:

0.0690

AC:

1804

AN:

26136

East Asian (EAS)

AF:

0.427

AC:

16911

AN:

39632

South Asian (SAS)

AF:

0.178

AC:

15382

AN:

86220

European-Finnish (FIN)

AF:

0.140

AC:

7477

AN:

53390

Middle Eastern (MID)

AF:

0.0330

AC:

190

AN:

5754

European-Non Finnish (NFE)

AF:

0.0863

AC:

96009

AN:

1111868

Other (OTH)

AF:

0.107

AC:

6469

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

8106

16211

24317

32422

40528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3798

7596

11394

15192

18990

<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:

0.0984

AC:

14970

AN:

152178

Hom.:

1256

Cov.:

AF XY:

0.105

AC XY:

7806

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.0252

AC:

1048

AN:

41540

American (AMR)

AF:

0.209

AC:

3197

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.0692

AC:

240

AN:

3470

East Asian (EAS)

AF:

0.368

AC:

1887

AN:

5132

South Asian (SAS)

AF:

0.200

AC:

967

AN:

4824

European-Finnish (FIN)

AF:

0.136

AC:

1443

AN:

10610

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0869

AC:

5911

AN:

68012

Other (OTH)

AF:

0.104

AC:

219

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

642

1284

1926

2568

3210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0937

Hom.:

2583

Bravo

AF:

0.103

TwinsUK

AF:

0.0925

AC:

343

ALSPAC

AF:

0.0921

AC:

355

ESP6500AA

AF:

0.0245

AC:

108

ESP6500EA

AF:

0.0779

AC:

670

ExAC

AF:

0.141

AC:

17075

Asia WGS

AF:

0.260

AC:

901

AN:

3478

EpiCase

AF:

0.0731

EpiControl

AF:

0.0747

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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 01, 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

Jun 15, 2021

Pars Genome 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. -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Thr4220Ala in exon 73 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 7.8% (670/8600) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2277046). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27989800, 23678272) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Benign

-0.12

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.10

PhyloP100

5.1

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.2

REVEL

Benign

0.060

Sift

Benign

0.046

Polyphen

0.0080

Vest4

0.25

MPC

0.26

ClinPred

0.029

GERP RS

4.3

Varity_R

0.41

gMVP

0.79

Mutation Taster

=83/17

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