rs145974361

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PP5_Moderate

The NM_001206927.2(DNAH8):c.6131+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,507,322 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: 𝑓 0.000076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.76

Publications

3 publications found

Variant links:

Genes affected

DNAH8 (HGNC:2952): (dynein axonemal heavy chain 8) The protein encoded by this gene is a heavy chain of an axonemal dynein involved in sperm and respiratory cilia motility. Axonemal dyneins generate force through hydrolysis of ATP and binding to microtubules. [provided by RefSeq, Jan 2012]

DNAH8 Gene-Disease associations (from GenCC):

spermatogenic failure 46
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
spermatogenic failure 5
Inheritance: AR Classification: MODERATE Submitted by: Franklin by Genoox
primary ciliary dyskinesia
Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

DNAH8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PP5

Variant 6-38860630-G-A is Pathogenic according to our data. Variant chr6-38860630-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 581228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH8	NM_001206927.2 link	c.6131+1G>A		splice_donor_variant, intron_variant	Intron 43 of 92	ENST00000327475.11	NP_001193856.1	Q96JB1Q8IU65A0A075B6F3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH8	ENST00000327475.11 link	c.6131+1G>A	splice_donor_variant, intron_variant	Intron 43 of 92	5	NM_001206927.2	ENSP00000333363.7	A0A075B6F3
DNAH8	ENST00000359357.7 link	c.5480+1G>A	splice_donor_variant, intron_variant	Intron 41 of 90	2		ENSP00000352312.3	Q96JB1-1
DNAH8	ENST00000449981.6 link	c.6131+1G>A	splice_donor_variant, intron_variant	Intron 42 of 81	5		ENSP00000415331.2	H0Y7V4

Frequencies

GnomAD3 genomes

AF:

0.0000755

AC:

AN:

145606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000136

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000586

AC:

AN:

170658

AF XY:

0.0000211

show subpopulations

Gnomad AFR exome

AF:

0.0000882

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

174

AN:

1361716

Hom.:

Cov.:

AF XY:

0.000120

AC XY:

AN XY:

673830

show subpopulations

African (AFR)

AF:

0.0000362

AC:

AN:

27652

American (AMR)

AF:

0.00

AC:

AN:

23062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23194

East Asian (EAS)

AF:

0.00

AC:

AN:

34264

South Asian (SAS)

AF:

0.00

AC:

AN:

66862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52130

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.000159

AC:

171

AN:

1072754

Other (OTH)

AF:

0.0000356

AC:

AN:

56250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000755

AC:

AN:

145606

Hom.:

Cov.:

AF XY:

0.000113

AC XY:

AN XY:

70778

show subpopulations

African (AFR)

AF:

0.0000502

AC:

AN:

39816

American (AMR)

AF:

0.00

AC:

AN:

13864

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3402

East Asian (EAS)

AF:

0.00

AC:

AN:

4672

South Asian (SAS)

AF:

0.00

AC:

AN:

4394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10048

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.000136

AC:

AN:

66208

Other (OTH)

AF:

0.00

AC:

AN:

2000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.0000838

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Pathogenic:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects a donor splice site in intron 43 of the DNAH8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DNAH8 are known to be pathogenic (PMID: 24307375, 32619401, 32681648). This variant is present in population databases (rs145974361, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DNAH8-related conditions. ClinVar contains an entry for this variant (Variation ID: 581228). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

PhyloP100

9.8

GERP RS

5.4

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.82

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.82

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over