NM_001369.3:c.6264C>T

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.6264C>T(p.Ala2088Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,658 control chromosomes in the GnomAD database, including 114,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2088A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 12283 hom., cov: 33)

Exomes 𝑓: 0.37 ( 101984 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.832

Publications

11 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=-0.62).

BP6

Variant 5-13829690-G-A is Benign according to our data. Variant chr5-13829690-G-A is described in ClinVar as Benign. ClinVar VariationId is 163145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.832 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.6264C>T	p.Ala2088Ala	synonymous_variant	Exon 38 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.6264C>T	p.Ala2088Ala	synonymous_variant	Exon 38 of 79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 link	c.6219C>T	p.Ala2073Ala	synonymous_variant	Exon 38 of 79			ENSP00000505288.1	A0A7P0Z455
DNAH5	ENST00000683090.1 link	n.1195C>T		non_coding_transcript_exon_variant	Exon 3 of 7

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60495

AN:

151858

Hom.:

12267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.456

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.400

GnomAD2 exomes

AF:

0.385

AC:

96523

AN:

250998

AF XY:

0.379

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.373

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.624

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.371

AC:

541740

AN:

1460680

Hom.:

101984

Cov.:

AF XY:

0.369

AC XY:

267886

AN XY:

726712

show subpopulations

African (AFR)

AF:

0.459

AC:

15365

AN:

33452

American (AMR)

AF:

0.378

AC:

16884

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

9392

AN:

26134

East Asian (EAS)

AF:

0.562

AC:

22319

AN:

39690

South Asian (SAS)

AF:

0.330

AC:

28419

AN:

86246

European-Finnish (FIN)

AF:

0.328

AC:

17488

AN:

53396

Middle Eastern (MID)

AF:

0.335

AC:

1933

AN:

5762

European-Non Finnish (NFE)

AF:

0.366

AC:

407021

AN:

1110926

Other (OTH)

AF:

0.380

AC:

22919

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

17736

35472

53207

70943

88679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12990

25980

38970

51960

64950

<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:

0.398

AC:

60548

AN:

151978

Hom.:

12283

Cov.:

AF XY:

0.396

AC XY:

29383

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.461

AC:

19099

AN:

41420

American (AMR)

AF:

0.383

AC:

5855

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.366

AC:

1270

AN:

3470

East Asian (EAS)

AF:

0.610

AC:

3151

AN:

5166

South Asian (SAS)

AF:

0.331

AC:

1590

AN:

4806

European-Finnish (FIN)

AF:

0.317

AC:

3351

AN:

10556

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.366

AC:

24884

AN:

67970

Other (OTH)

AF:

0.397

AC:

837

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1864

3729

5593

7458

9322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

580

1160

1740

2320

2900

<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:

0.364

Hom.:

7318

Bravo

AF:

0.411

Asia WGS

AF:

0.454

AC:

1578

AN:

3478

EpiCase

AF:

0.370

EpiControl

AF:

0.364

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

Ala2088Ala in exon 38 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 45.6% (2011/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1348689). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

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 10, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 3

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.8

(source)

DANN

Benign

0.64

PhyloP100

-0.83

Mutation Taster

=71/29

polymorphism

(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