17-11598799-CTT-CT

Variant names:

• chr17-11598799-CT-C
• rs769795916
• NM_001372.4:c.308delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001372.4(DNAH9):​c.308delT​(p.Phe103SerfsTer31) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,479,728 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: DNAH9 NM_001372.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 2.46
• Publications: 0 publications found

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: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 17-11598799-CT-C is Pathogenic according to our data. Variant chr17-11598799-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1455970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.308delT	p.Phe103SerfsTer31	frameshift	Exon 1 of 69	NP_001363.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH9	ENST00000262442.9	TSL:1 MANE Select	c.308delT	p.Phe103SerfsTer31	frameshift	Exon 1 of 69	ENSP00000262442.3
	DNAH9	ENST00000579406.1	TSL:1	n.335delT		non_coding_transcript_exon	Exon 1 of 8
	DNAH9	ENST00000454412.6	TSL:5	c.308delT	p.Phe103SerfsTer31	frameshift	Exon 1 of 68	ENSP00000414874.2

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152110 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000703 AC: 57 AN: 81052 AF XY: 0.000708

Gnomad AFR exome AF: 0.000991

Gnomad AMR exome AF: 0.000438

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.000473

Gnomad FIN exome AF: 0.000757

Gnomad NFE exome AF: 0.00122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000614 AC: 815 AN: 1327512 Hom.: 1 Cov.: 33 AF XY: 0.000571 AC XY: 372 AN XY: 652050

African (AFR) AF: 0.000260 AC: 7 AN: 26890

American (AMR) AF: 0.000396 AC: 11 AN: 27764

Ashkenazi Jewish (ASJ) AF: 0.000400 AC: 9 AN: 22502

East Asian (EAS) AF: 0.000295 AC: 9 AN: 30494

South Asian (SAS) AF: 0.000334 AC: 25 AN: 74838

European-Finnish (FIN) AF: 0.000175 AC: 6 AN: 34240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5084

European-Non Finnish (NFE) AF: 0.000687 AC: 722 AN: 1050878

Other (OTH) AF: 0.000474 AC: 26 AN: 54822

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74432

African (AFR) AF: 0.000457 AC: 19 AN: 41558

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5126

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000365 Hom.: 0

Bravo AF: 0.000484

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Ciliary dyskinesia, primary, 40 (4)
1	-	-	DNAH9-related disorder (1)
1	-	-	not provided (1)
-	1	-	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=38/162	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs769795916; hg19: chr17-11502116; COSMIC: COSV52351003;