17-11598568-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001372.4(DNAH9):c.70C>T(p.Arg24Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000835 in 1,197,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R24R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.4e-7 (0 hom.)
• Consequence: DNAH9 NM_001372.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.244

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 58 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-11598568-C-T is Pathogenic according to our data. Variant chr17-11598568-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2782150.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH9	NM_001372.4	c.70C>T	p.Arg24Ter	stop_gained	1/69	ENST00000262442.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH9	ENST00000262442.9	c.70C>T	p.Arg24Ter	stop_gained	1/69	1	NM_001372.4	P1
DNAH9	ENST00000579406.1	n.97C>T		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6	c.70C>T	p.Arg24Ter	stop_gained	1/68	5
DNAH9	ENST00000579828.5	c.70C>T	p.Arg24Ter	stop_gained	1/4	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.35e-7 AC: 1 AN: 1197330 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 585708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 27, 2023

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg24*) in the DNAH9 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH9 are known to be pathogenic (PMID: 30471718). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Benign	0.12
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.28	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.077
GERP RS		-2.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-11501885; COSMIC: COSV52352465;