chr5-13902136-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_001369.3(DNAH5):c.1647C>G(p.Asn549Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,599,012 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N549N) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 33)

Exomes 𝑓: 0.015 ( 169 hom. )

Consequence

DNAH5
NM_001369.3 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.451

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: 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 -14 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BP6

Variant 5-13902136-G-C is Benign according to our data. Variant chr5-13902136-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1613/152220) while in subpopulation NFE AF = 0.016 (1088/68002). AF 95% confidence interval is 0.0152. There are 17 homozygotes in GnomAd4. There are 715 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AD,AR gene

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.1647C>G	p.Asn549Lys	missense splice_region	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.1647C>G	p.Asn549Lys	missense splice_region	Exon 13 of 79	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.1602C>G	p.Asn534Lys	missense splice_region	Exon 13 of 79	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1614

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00319

Gnomad AMI

AF:

0.0746

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.0282

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.00208

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.0103

AC:

2494

AN:

241900

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00243

Gnomad AMR exome

AF:

0.00842

Gnomad ASJ exome

AF:

0.0295

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00246

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0148

AC:

21380

AN:

1446792

Hom.:

169

Cov.:

AF XY:

0.0146

AC XY:

10481

AN XY:

719972

show subpopulations

African (AFR)

AF:

0.00252

AC:

AN:

33314

American (AMR)

AF:

0.00884

AC:

392

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.0300

AC:

774

AN:

25770

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39496

South Asian (SAS)

AF:

0.00342

AC:

292

AN:

85336

European-Finnish (FIN)

AF:

0.00263

AC:

138

AN:

52390

Middle Eastern (MID)

AF:

0.0105

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.0170

AC:

18724

AN:

1100556

Other (OTH)

AF:

0.0153

AC:

915

AN:

59854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

870

1740

2611

3481

4351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

724

1448

2172

2896

3620

<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:

0.0106

AC:

1613

AN:

152220

Hom.:

Cov.:

AF XY:

0.00961

AC XY:

715

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00318

AC:

132

AN:

41530

American (AMR)

AF:

0.0105

AC:

160

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.00290

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00208

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0274

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0160

AC:

1088

AN:

68002

Other (OTH)

AF:

0.00992

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0145

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0159

AC:

136

ExAC

AF:

0.00973

AC:

1180

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (3)

not provided (2)

not specified (2)

Primary ciliary dyskinesia 3 (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.070

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

PhyloP100

0.45

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Benign

0.92

Polyphen

0.0

Vest4

0.13

MutPred

0.51

Gain of ubiquitination at N549 (P = 0.0337)

MPC

0.44

ClinPred

0.013

GERP RS

-1.1

Varity_R

0.11

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.81

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.81

Position offset: -1

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