5-13886135-CAAAAAAAAAA-CAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001369.3(DNAH5):c.2578-10_2578-7delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0236 in 1,316,524 control chromosomes in the GnomAD database, including 14 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0064 ( 11 hom., cov: 0)

Exomes 𝑓: 0.025 ( 3 hom. )

Consequence

DNAH5
NM_001369.3 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.52

Publications

2 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 -16 ACMG points.

BP6

Variant 5-13886135-CAAAA-C is Benign according to our data. Variant chr5-13886135-CAAAA-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 402730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00641 (794/123836) while in subpopulation AFR AF = 0.0211 (712/33796). AF 95% confidence interval is 0.0198. There are 11 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.2578-10_2578-7delTTTT		splice_region_variant, intron_variant	Intron 17 of 78	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
DNAH5	ENST00000265104.5 link	c.2578-10_2578-7delTTTT	splice_region_variant, intron_variant	Intron 17 of 78	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1 link	c.2533-10_2533-7delTTTT	splice_region_variant, intron_variant	Intron 17 of 78			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2 link	n.254-10453_254-10450delAAAA	intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1 link	n.214-10453_214-10450delAAAA	intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.00640

AC:

793

AN:

123858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0211

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00274

Gnomad ASJ

AF:

0.000664

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000516

Gnomad FIN

AF:

0.00284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000374

Gnomad OTH

AF:

0.00362

GnomAD2 exomes

AF:

0.0300

AC:

1847

AN:

61536

AF XY:

0.0287

show subpopulations

Gnomad AFR exome

AF:

0.0376

Gnomad AMR exome

AF:

0.0501

Gnomad ASJ exome

AF:

0.0272

Gnomad EAS exome

AF:

0.00728

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0246

Gnomad OTH exome

AF:

0.0265

GnomAD4 exome

AF:

0.0254

AC:

30317

AN:

1192688

Hom.:

AF XY:

0.0250

AC XY:

14725

AN XY:

589490

show subpopulations

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

African (AFR)

AF:

0.0387

AC:

1014

AN:

26208

American (AMR)

AF:

0.0389

AC:

1035

AN:

26638

Ashkenazi Jewish (ASJ)

AF:

0.0289

AC:

586

AN:

20282

East Asian (EAS)

AF:

0.00708

AC:

229

AN:

32364

South Asian (SAS)

AF:

0.0229

AC:

1465

AN:

63918

European-Finnish (FIN)

AF:

0.0259

AC:

791

AN:

30498

Middle Eastern (MID)

AF:

0.0324

AC:

112

AN:

3460

European-Non Finnish (NFE)

AF:

0.0253

AC:

23776

AN:

939654

Other (OTH)

AF:

0.0264

AC:

1309

AN:

49666

⚠️ 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: 0.289

Heterozygous variant carriers

2360

4719

7079

9438

11798

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

940

1880

2820

3760

4700

<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:

0.00641

AC:

794

AN:

123836

Hom.:

Cov.:

AF XY:

0.00678

AC XY:

398

AN XY:

58696

show subpopulations

African (AFR)

AF:

0.0211

AC:

712

AN:

33796

American (AMR)

AF:

0.00274

AC:

AN:

12048

Ashkenazi Jewish (ASJ)

AF:

0.000664

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.000519

AC:

AN:

3852

European-Finnish (FIN)

AF:

0.00284

AC:

AN:

5982

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000374

AC:

AN:

58852

Other (OTH)

AF:

0.00361

AC:

AN:

1662

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.0119

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 02, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 24, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, No homozygotes in ExAC, but on the low side of coverage. Gene is associated with PCD.

Primary ciliary dyskinesia

Benign:1

Sep 27, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism

(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