chr5-13894785-T-A

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.2296A>T(p.Ile766Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,613,488 control chromosomes in the GnomAD database, including 211,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I766M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.50 ( 19427 hom., cov: 32)

Exomes 𝑓: 0.51 ( 191617 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.01

Publications

33 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:

DNAH5-AS1 (HGNC:40187):

DNAH5-AS1 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=2.2438915E-5).

BP6

Variant 5-13894785-T-A is Benign according to our data. Variant chr5-13894785-T-A is described in ClinVar as Benign. ClinVar VariationId is 178753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.591 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.2296A>T	p.Ile766Leu	missense	Exon 16 of 79	NP_001360.1	Q8TE73
	DNAH5-AS1	NR_199035.1		n.118-1804T>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.2296A>T	p.Ile766Leu	missense	Exon 16 of 79	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1		c.2251A>T	p.Ile751Leu	missense	Exon 16 of 79	ENSP00000505288.1	A0A7P0Z455
DNAH5-AS1	ENST00000503244.2	TSL:4	n.254-1804T>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76485

AN:

151852

Hom.:

19411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.524

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.610

Gnomad FIN

AF:

0.449

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.506

GnomAD2 exomes

AF:

0.500

AC:

125490

AN:

251066

AF XY:

0.508

show subpopulations

Gnomad AFR exome

AF:

0.534

Gnomad AMR exome

AF:

0.497

Gnomad ASJ exome

AF:

0.526

Gnomad EAS exome

AF:

0.238

Gnomad FIN exome

AF:

0.459

Gnomad NFE exome

AF:

0.509

Gnomad OTH exome

AF:

0.495

GnomAD4 exome

AF:

0.509

AC:

743312

AN:

1461518

Hom.:

191617

Cov.:

AF XY:

0.512

AC XY:

372466

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.538

AC:

17993

AN:

33472

American (AMR)

AF:

0.497

AC:

22227

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

13660

AN:

26128

East Asian (EAS)

AF:

0.242

AC:

9617

AN:

39688

South Asian (SAS)

AF:

0.625

AC:

53932

AN:

86252

European-Finnish (FIN)

AF:

0.457

AC:

24387

AN:

53348

Middle Eastern (MID)

AF:

0.541

AC:

3123

AN:

5768

European-Non Finnish (NFE)

AF:

0.511

AC:

568128

AN:

1111764

Other (OTH)

AF:

0.501

AC:

30245

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

20844

41687

62531

83374

104218

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16416

32832

49248

65664

82080

<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:

0.504

AC:

76550

AN:

151970

Hom.:

19427

Cov.:

AF XY:

0.502

AC XY:

37314

AN XY:

74278

show subpopulations

African (AFR)

AF:

0.530

AC:

21956

AN:

41456

American (AMR)

AF:

0.500

AC:

7632

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.527

AC:

1830

AN:

3470

East Asian (EAS)

AF:

0.243

AC:

1257

AN:

5182

South Asian (SAS)

AF:

0.609

AC:

2935

AN:

4816

European-Finnish (FIN)

AF:

0.449

AC:

4730

AN:

10538

Middle Eastern (MID)

AF:

0.578

AC:

170

AN:

294

European-Non Finnish (NFE)

AF:

0.508

AC:

34494

AN:

67936

Other (OTH)

AF:

0.508

AC:

1068

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1968

3936

5905

7873

9841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

680

1360

2040

2720

3400

<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:

0.507

Hom.:

14802

Bravo

AF:

0.505

TwinsUK

AF:

0.509

AC:

1887

ALSPAC

AF:

0.528

AC:

2035

ESP6500AA

AF:

0.533

AC:

2349

ESP6500EA

AF:

0.508

AC:

4368

ExAC

AF:

0.507

AC:

61573

Asia WGS

AF:

0.453

AC:

1577

AN:

3478

EpiCase

AF:

0.510

EpiControl

AF:

0.512

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Primary ciliary dyskinesia (3)

Primary ciliary dyskinesia 3 (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.096

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.51

MetaRNN

Benign

0.000022

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PhyloP100

3.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.088

Sift

Benign

0.31

Polyphen

0.0010

Vest4

0.088

MutPred

0.44

Gain of ubiquitination at K765 (P = 0.1047)

MPC

0.093

ClinPred

0.027

GERP RS

4.4

Varity_R

0.18

gMVP

0.26

Mutation Taster

=86/14

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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