rs1530498

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.1672A>G(p.Thr558Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,603,616 control chromosomes in the GnomAD database, including 131,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. T558T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.35 ( 10499 hom., cov: 33)

Exomes 𝑓: 0.40 ( 121053 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.21

Publications

34 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
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=2.1918752E-6).

BP6

Variant 5-13902111-T-C is Benign according to our data. Variant chr5-13902111-T-C is described in ClinVar as Benign. ClinVar VariationId is 163157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.1672A>G	p.Thr558Ala	missense	Exon 13 of 79	NP_001360.1	Q8TE73

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.1672A>G	p.Thr558Ala	missense	Exon 13 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.1627A>G	p.Thr543Ala	missense	Exon 13 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.353

AC:

53630

AN:

152060

Hom.:

10497

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.387

Gnomad ASJ

AF:

0.422

Gnomad EAS

AF:

0.761

Gnomad SAS

AF:

0.322

Gnomad FIN

AF:

0.366

Gnomad MID

AF:

0.430

Gnomad NFE

AF:

0.407

Gnomad OTH

AF:

0.360

GnomAD2 exomes

AF:

0.399

AC:

97352

AN:

244236

AF XY:

0.396

show subpopulations

Gnomad AFR exome

AF:

0.183

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.429

Gnomad EAS exome

AF:

0.761

Gnomad FIN exome

AF:

0.370

Gnomad NFE exome

AF:

0.402

Gnomad OTH exome

AF:

0.410

GnomAD4 exome

AF:

0.400

AC:

580750

AN:

1451438

Hom.:

121053

Cov.:

AF XY:

0.398

AC XY:

287102

AN XY:

721874

show subpopulations

African (AFR)

AF:

0.177

AC:

5918

AN:

33366

American (AMR)

AF:

0.384

AC:

17023

AN:

44324

Ashkenazi Jewish (ASJ)

AF:

0.429

AC:

11099

AN:

25898

East Asian (EAS)

AF:

0.758

AC:

29979

AN:

39538

South Asian (SAS)

AF:

0.305

AC:

26085

AN:

85626

European-Finnish (FIN)

AF:

0.378

AC:

19882

AN:

52616

Middle Eastern (MID)

AF:

0.421

AC:

2416

AN:

5740

European-Non Finnish (NFE)

AF:

0.402

AC:

444148

AN:

1104326

Other (OTH)

AF:

0.403

AC:

24200

AN:

60004

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

14837

29674

44512

59349

74186

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13738

27476

41214

54952

68690

<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:

0.352

AC:

53628

AN:

152178

Hom.:

10499

Cov.:

AF XY:

0.353

AC XY:

26254

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.193

AC:

8020

AN:

41550

American (AMR)

AF:

0.387

AC:

5919

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.422

AC:

1466

AN:

3472

East Asian (EAS)

AF:

0.762

AC:

3943

AN:

5176

South Asian (SAS)

AF:

0.322

AC:

1555

AN:

4828

European-Finnish (FIN)

AF:

0.366

AC:

3863

AN:

10568

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.407

AC:

27693

AN:

67980

Other (OTH)

AF:

0.360

AC:

759

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1748

3496

5243

6991

8739

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<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:

0.397

Hom.:

54253

Bravo

AF:

0.350

TwinsUK

AF:

0.406

AC:

1505

ALSPAC

AF:

0.386

AC:

1489

ESP6500AA

AF:

0.189

AC:

831

ESP6500EA

AF:

0.406

AC:

3481

ExAC

AF:

0.388

AC:

47069

Asia WGS

AF:

0.479

AC:

1664

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Primary ciliary dyskinesia (3)

not provided (2)

Primary ciliary dyskinesia 3 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.072

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0000022

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.5

PhyloP100

1.2

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.7

REVEL

Benign

0.080

Sift

Benign

0.79

Polyphen

0.0020

Vest4

0.082

MPC

0.26

ClinPred

0.015

GERP RS

2.6

Varity_R

0.19

gMVP

0.46

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over