17-11598501-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001372.4(DNAH9):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000498 in 1,204,918 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: DNAH9 NM_001372.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH9	NM_001372.4	c.3G>A	p.Met1?	start_lost	1/69	ENST00000262442.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH9	ENST00000262442.9	c.3G>A	p.Met1?	start_lost	1/69	1	NM_001372.4	P1
DNAH9	ENST00000579406.1	n.30G>A		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6	c.3G>A	p.Met1?	start_lost	1/68	5
DNAH9	ENST00000579828.5	c.3G>A	p.Met1?	start_lost	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000498 AC: 6 AN: 1204918 Hom.: 0 Cov.: 33 AF XY: 0.00000513 AC XY: 3 AN XY: 585116

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: 0.00000604

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2021

This sequence change affects the initiator methionine of the DNAH9 mRNA. The next in-frame methionine is located at codon 34. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	0.0060	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	20
Dann	Benign	0.90
DEOGEN2	Benign	0.0063	T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.50	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PROVEAN	Benign	-0.54	N;.;N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D;.;D
Polyphen		0.039	B;.;P
Vest4		0.60
MutPred		0.94		Gain of catalytic residue at M1 (P = 0.0516);Gain of catalytic residue at M1 (P = 0.0516);Gain of catalytic residue at M1 (P = 0.0516);
MVP		0.40
ClinPred		0.36	T
GERP RS		3.6
Varity_R		0.87
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs1359925162; hg19: chr17-11501818;