Genetic Variant DNAH5:c.5272-16_5272-15dupTT (chr5-13841918-C-CAA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001369.3(DNAH5):c.5272-16_5272-15dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.015 ( 52 hom., cov: 0)

Exomes 𝑓: 0.019 ( 4 hom. )

Consequence

DNAH5
NM_001369.3 intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.617

Publications

0 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.129 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.5272-16_5272-15dupTT		intron	N/A	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.5272-15_5272-14insTT		intron	N/A	ENSP00000265104.4	Q8TE73
	DNAH5	ENST00000681290.1		c.5227-15_5227-14insTT		intron	N/A	ENSP00000505288.1	A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.0149

AC:

1561

AN:

104512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0121

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.00852

Gnomad ASJ

AF:

0.0155

Gnomad EAS

AF:

0.140

Gnomad SAS

AF:

0.0219

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00925

Gnomad OTH

AF:

0.0122

GnomAD4 exome

AF:

0.0188

AC:

9070

AN:

483186

Hom.:

Cov.:

AF XY:

0.0190

AC XY:

4974

AN XY:

261124

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0146

AC:

181

AN:

12424

American (AMR)

AF:

0.0180

AC:

342

AN:

19022

Ashkenazi Jewish (ASJ)

AF:

0.0160

AC:

220

AN:

13720

East Asian (EAS)

AF:

0.0438

AC:

1154

AN:

26324

South Asian (SAS)

AF:

0.0336

AC:

1500

AN:

44638

European-Finnish (FIN)

AF:

0.0219

AC:

579

AN:

26480

Middle Eastern (MID)

AF:

0.0218

AC:

AN:

1976

European-Non Finnish (NFE)

AF:

0.0147

AC:

4608

AN:

313480

Other (OTH)

AF:

0.0176

AC:

443

AN:

25122

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.326

Heterozygous variant carriers

560

1120

1679

2239

2799

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

180

240

300

<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:

0.0149

AC:

1560

AN:

104506

Hom.:

Cov.:

AF XY:

0.0163

AC XY:

768

AN XY:

47190

show subpopulations

African (AFR)

AF:

0.0121

AC:

341

AN:

28146

American (AMR)

AF:

0.00852

AC:

AN:

8688

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

AN:

2960

East Asian (EAS)

AF:

0.140

AC:

434

AN:

3100

South Asian (SAS)

AF:

0.0215

AC:

AN:

2692

European-Finnish (FIN)

AF:

0.0291

AC:

AN:

1888

Middle Eastern (MID)

AF:

0.0195

AC:

AN:

154

European-Non Finnish (NFE)

AF:

0.00925

AC:

506

AN:

54722

Other (OTH)

AF:

0.0122

AC:

AN:

1392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

149

198

248

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.62

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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chr5-13841919-AA-AAAA

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