Genetic Variant DNAH8:c.9349-1G>T (chr6-38907955-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_001206927.2(DNAH8):c.9349-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,628 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: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DNAH8
NM_001206927.2 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.99

Publications

0 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 links:

DNAH8-AS1 (HGNC:40188): (DNAH8 antisense RNA 1)

DNAH8-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.011682243 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-38907955-G-T is Pathogenic according to our data. Variant chr6-38907955-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 454609.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206927.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DNAH8	NM_001206927.2	MANE Select	c.9349-1G>T	splice_acceptor intron	N/A	NP_001193856.1
DNAH8	NM_001371.4		c.8698-1G>T	splice_acceptor intron	N/A	NP_001362.2
DNAH8-AS1	NR_038401.1		n.783-118C>A	intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
DNAH8	ENST00000327475.11	TSL:5 MANE Select	c.9349-1G>T	splice_acceptor intron	N/A	ENSP00000333363.7
DNAH8	ENST00000359357.7	TSL:2	c.8698-1G>T	splice_acceptor intron	N/A	ENSP00000352312.3
DNAH8	ENST00000449981.6	TSL:5	c.9349-1G>T	splice_acceptor intron	N/A	ENSP00000415331.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1439628

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715250

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32198

American (AMR)

AF:

0.00

AC:

AN:

40638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25330

East Asian (EAS)

AF:

0.00

AC:

AN:

38660

South Asian (SAS)

AF:

0.00

AC:

AN:

81728

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5688

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103060

Other (OTH)

AF:

0.0000168

AC:

AN:

59452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.3

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

PhyloP100

8.0

GERP RS

5.7

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)

0.97

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.97

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over