rs115004914

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001369.3(DNAH5):c.2253C>A(p.Asn751Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 1,612,604 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0052 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0073 ( 130 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.655

Publications

12 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:

ENSG00000251423 (HGNC:40187):

ENSG00000251423 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=0.0028903186).

BP6

Variant 5-13900212-G-T is Benign according to our data. Variant chr5-13900212-G-T is described in ClinVar as Benign. ClinVar VariationId is 178754.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00517 (787/152296) while in subpopulation SAS AF = 0.0332 (160/4824). AF 95% confidence interval is 0.029. There are 2 homozygotes in GnomAd4. There are 428 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.2253C>A	p.Asn751Lys	missense_variant	Exon 15 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.2253C>A	p.Asn751Lys	missense_variant	Exon 15 of 79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 link	c.2208C>A	p.Asn736Lys	missense_variant	Exon 15 of 79			ENSP00000505288.1	A0A7P0Z455
ENSG00000251423	ENST00000503244.2 link	n.3088G>T		non_coding_transcript_exon_variant	Exon 3 of 3	4
ENSG00000251423	ENST00000637153.1 link	n.3048G>T		non_coding_transcript_exon_variant	Exon 3 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.00520

AC:

792

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0338

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00557

Gnomad OTH

AF:

0.00623

GnomAD2 exomes

AF:

0.00972

AC:

2439

AN:

250898

AF XY:

0.0113

show subpopulations

Gnomad AFR exome

AF:

0.000557

Gnomad AMR exome

AF:

0.00526

Gnomad ASJ exome

AF:

0.0140

Gnomad EAS exome

AF:

0.00212

Gnomad FIN exome

AF:

0.00300

Gnomad NFE exome

AF:

0.00650

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.00728

AC:

10631

AN:

1460308

Hom.:

130

Cov.:

AF XY:

0.00847

AC XY:

6155

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.00179

AC:

AN:

33446

American (AMR)

AF:

0.00541

AC:

242

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

356

AN:

26120

East Asian (EAS)

AF:

0.00113

AC:

AN:

39690

South Asian (SAS)

AF:

0.0391

AC:

3370

AN:

86172

European-Finnish (FIN)

AF:

0.00300

AC:

160

AN:

53412

Middle Eastern (MID)

AF:

0.0410

AC:

236

AN:

5754

European-Non Finnish (NFE)

AF:

0.00505

AC:

5605

AN:

1110654

Other (OTH)

AF:

0.00923

AC:

557

AN:

60340

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

Heterozygous variant carriers

522

1044

1566

2088

2610

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

220

440

660

880

1100

<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:

0.00517

AC:

787

AN:

152296

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

428

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.000914

AC:

AN:

41564

American (AMR)

AF:

0.00765

AC:

117

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0135

AC:

AN:

3472

East Asian (EAS)

AF:

0.00231

AC:

AN:

5188

South Asian (SAS)

AF:

0.0332

AC:

160

AN:

4824

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00557

AC:

379

AN:

68024

Other (OTH)

AF:

0.00569

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

113

150

188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<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:

0.00425

Hom.:

Bravo

AF:

0.00465

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00581

AC:

ExAC

AF:

0.0101

AC:

1232

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.00638

EpiControl

AF:

0.00711

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH5: BP4, BS1, BS2 -

Feb 27, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31213628) -

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:3

Dec 23, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asn751Lys in exon 15 of DNAH5: This variant is not expected to have clinical s ignificance because it has been identified in 3.8% (635/16496) of South Asian ch romosomes, including 18 homozygotes, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs115004914). -

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

- -

Jun 09, 2015

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:2

Jan 12, 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. -

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.045

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.085

PhyloP100

0.66

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.59

REVEL

Benign

0.084

Sift

Benign

0.98

Polyphen

0.0

Vest4

0.16

MutPred

0.58

Gain of disorder (P = 0.06);

MPC

0.34

ClinPred

0.011

GERP RS

1.3

Varity_R

0.056

gMVP

0.21

Mutation Taster

=92/8

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