17-11598569-G-A

Position:

• chr17-11598569-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001372.4(DNAH9):​c.71G>A​(p.Arg24Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000207 in 1,253,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: DNAH9 NM_001372.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.829

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26686722).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH9	NM_001372.4	c.71G>A	p.Arg24Gln	missense_variant	1/69	ENST00000262442.9	NP_001363.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH9	ENST00000262442.9	c.71G>A	p.Arg24Gln	missense_variant	1/69	1	NM_001372.4	ENSP00000262442	P1
DNAH9	ENST00000579406.1	n.98G>A		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6	c.71G>A	p.Arg24Gln	missense_variant	1/68	5		ENSP00000414874
DNAH9	ENST00000579828.5	c.71G>A	p.Arg24Gln	missense_variant	1/4	2		ENSP00000463782

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000207 AC: 26 AN: 1253888 Hom.: 0 Cov.: 33 AF XY: 0.0000228 AC XY: 14 AN XY: 613040

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: 0.0000255

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

May 18, 2023

This variant is not present in population databases (gnomAD no frequency). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DNAH9 protein function. This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 24 of the DNAH9 protein (p.Arg24Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;.
Eigen	Benign	-0.061
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.61	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Pathogenic	2.9	M;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;.;D
Sift4G	Benign	0.24	.;T;.
Polyphen		1.0	D;.;B
Vest4		0.20
MVP		0.70
MPC		0.10
ClinPred		0.98	D
GERP RS		3.7
Varity_R		0.37
gMVP		0.70

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: rs759458594; hg19: chr17-11501886;