Genetic Variant DNAH5:c.2578-12_2578-7delTTTTTT (chr5-13886135-CAAAAAA-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001369.3(DNAH5):c.2578-12_2578-7delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000561 in 1,338,960 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00061 ( 0 hom. )

Consequence

DNAH5
NM_001369.3 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: Uncertain_significance. The variant received 0 ACMG points.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.2578-12_2578-7delTTTTTT		splice_region intron	N/A	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.118-10440_118-10435delAAAAAA		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.2578-12_2578-7delTTTTTT	splice_region intron	N/A	ENSP00000265104.4
DNAH5	ENST00000681290.1		c.2533-12_2533-7delTTTTTT	splice_region intron	N/A	ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	TSL:4	n.254-10453_254-10448delAAAAAA	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000888

AC:

AN:

123876

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000296

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000830

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000609

AC:

740

AN:

1215084

Hom.:

AF XY:

0.000566

AC XY:

340

AN XY:

600854

show subpopulations

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

African (AFR)

AF:

0.00236

AC:

AN:

26708

American (AMR)

AF:

0.000659

AC:

AN:

27308

Ashkenazi Jewish (ASJ)

AF:

0.000672

AC:

AN:

20826

East Asian (EAS)

AF:

0.0000910

AC:

AN:

32958

South Asian (SAS)

AF:

0.000703

AC:

AN:

65394

European-Finnish (FIN)

AF:

0.000320

AC:

AN:

31292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3534

European-Non Finnish (NFE)

AF:

0.000569

AC:

544

AN:

956296

Other (OTH)

AF:

0.000827

AC:

AN:

50768

⚠️ 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: 0.258

Heterozygous variant carriers

188

283

377

471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.0000888

AC:

AN:

123876

Hom.:

Cov.:

AF XY:

0.000119

AC XY:

AN XY:

58712

show subpopulations

African (AFR)

AF:

0.000296

AC:

AN:

33766

American (AMR)

AF:

0.0000830

AC:

AN:

12044

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3012

East Asian (EAS)

AF:

0.00

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

3878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5986

Middle Eastern (MID)

AF:

0.00

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

58872

Other (OTH)

AF:

0.00

AC:

AN:

1656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0127

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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