17-11598568-C-G

Position:

chr17-11598568-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001372.4(DNAH9):c.70C>G(p.Arg24Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000983 in 1,343,384 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 2 hom. )

Consequence

DNAH9
NM_001372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.244

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06858349).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH9	NM_001372.4 linkuse as main transcript	c.70C>G	p.Arg24Gly	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 linkuse as main transcript	c.70C>G	p.Arg24Gly	missense_variant	1/69	1	NM_001372.4	ENSP00000262442	P1	Q9NYC9-1
DNAH9	ENST00000579406.1 linkuse as main transcript	n.97C>G		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6 linkuse as main transcript	c.70C>G	p.Arg24Gly	missense_variant	1/68	5		ENSP00000414874
DNAH9	ENST00000579828.5 linkuse as main transcript	c.70C>G	p.Arg24Gly	missense_variant	1/4	2		ENSP00000463782

Frequencies

GnomAD3 genomes

AF:

0.0000274

AC:

AN:

146056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000684

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000427

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000284

AC:

AN:

28186

Hom.:

AF XY:

0.000357

AC XY:

AN XY:

16816

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000800

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000277

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

128

AN:

1197328

Hom.:

Cov.:

AF XY:

0.000145

AC XY:

AN XY:

585708

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000136

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000647

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000835

Gnomad4 OTH exome

AF:

0.000141

GnomAD4 genome

AF:

0.0000274

AC:

AN:

146056

Hom.:

Cov.:

AF XY:

0.0000422

AC XY:

AN XY:

71162

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000684

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000427

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000155

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.0000903

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.70C>G (p.R24G) alteration is located in exon 1 (coding exon 1) of the DNAH9 gene. This alteration results from a C to G substitution at nucleotide position 70, causing the arginine (R) at amino acid position 24 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 20, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 24 of the DNAH9 protein (p.Arg24Gly). This variant is present in population databases (rs774227660, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with DNAH9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1350370). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.34

T;.;.

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.80

T;T;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.069

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

2.9

M;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.8

D;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0030

D;.;D

Sift4G

Benign

0.11

.;T;.

Polyphen

1.0

D;.;B

Vest4

0.43

MutPred

0.65

Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);Loss of stability (P = 0.0145);

MVP

0.62

MPC

0.11

ClinPred

0.39

GERP RS

-2.0

Varity_R

0.34

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over