Genetic Variant DNAH9:p.Arg24GlyfsTer28 (chr17-11598539-A-ACGCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGAC) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001372.4(DNAH9):c.68_69insCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGACCG(p.Arg24GlyfsTer28) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000239 in 1,252,996 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R23R) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

DNAH9
NM_001372.4 frameshift

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.735

Publications

0 publications found

Variant links:

Genes affected

DNAH9 (HGNC:2953): (dynein axonemal heavy chain 9) This gene encodes the heavy chain subunit of axonemal dynein, a large multi-subunit molecular motor. Axonemal dynein attaches to microtubules and hydrolyzes ATP to mediate the movement of cilia and flagella. The gene expresses at least two transcript variants; additional variants have been described, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

DNAH9 Gene-Disease associations (from GenCC):

ciliary dyskinesia, primary, 40
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
situs inversus
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
schizophrenia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

DNAH9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 99 pathogenic variants in the truncated region.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001372.4. 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
	DNAH9	NM_001372.4	MANE Select	c.68_69insCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGACCG	p.Arg24GlyfsTer28	frameshift	Exon 1 of 69	NP_001363.2	Q9NYC9-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH9	ENST00000262442.9	TSL:1 MANE Select	c.68_69insCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGACCG	p.Arg24GlyfsTer28	frameshift	Exon 1 of 69	ENSP00000262442.3	Q9NYC9-1
DNAH9	ENST00000579406.1	TSL:1	n.95_96insCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGACCG		non_coding_transcript_exon	Exon 1 of 8
DNAH9	ENST00000454412.6	TSL:5	c.68_69insCGGATGGGGAACCCGGCGCCGACCGCGGATGGGGAACCCGGCGCCGACCG	p.Arg24GlyfsTer28	frameshift	Exon 1 of 68	ENSP00000414874.2	E7EP17

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000239

AC:

AN:

1252996

Hom.:

Cov.:

AF XY:

0.00000490

AC XY:

AN XY:

611986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25000

American (AMR)

AF:

0.00

AC:

AN:

15952

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19198

East Asian (EAS)

AF:

0.00

AC:

AN:

28016

South Asian (SAS)

AF:

0.00

AC:

AN:

60086

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3856

European-Non Finnish (NFE)

AF:

0.00000294

AC:

AN:

1018944

Other (OTH)

AF:

0.00

AC:

AN:

51638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.73

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over