17-11598537-G-C

Position:

chr17-11598537-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001372.4(DNAH9):c.39G>C(p.Glu13Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,406,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 1 hom. )

Consequence

DNAH9
NM_001372.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.576

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0035793781).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH9	NM_001372.4 linkuse as main transcript	c.39G>C	p.Glu13Asp	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.39G>C	p.Glu13Asp	missense_variant	1/69	1	NM_001372.4	ENSP00000262442	P1	Q9NYC9-1
DNAH9	ENST00000579406.1 linkuse as main transcript	n.66G>C		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6 linkuse as main transcript	c.39G>C	p.Glu13Asp	missense_variant	1/68	5		ENSP00000414874
DNAH9	ENST00000579828.5 linkuse as main transcript	c.39G>C	p.Glu13Asp	missense_variant	1/4	2		ENSP00000463782

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000271

AC:

AN:

29540

Hom.:

AF XY:

0.000350

AC XY:

AN XY:

17164

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:

0.000970

Gnomad FIN exome

AF:

0.000561

Gnomad NFE exome

AF:

0.0000934

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000291

AC:

365

AN:

1254742

Hom.:

Cov.:

AF XY:

0.000339

AC XY:

208

AN XY:

612842

show subpopulations

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:

0.00124

Gnomad4 FIN exome

AF:

0.000658

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.000271

GnomAD4 genome

AF:

0.000243

AC:

AN:

152254

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00103

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.0000693

Hom.:

Bravo

AF:

0.000155

ExAC

AF:

0.000163

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

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

Nov 19, 2022

The c.39G>C (p.E13D) alteration is located in exon 1 (coding exon 1) of the DNAH9 gene. This alteration results from a G to C substitution at nucleotide position 39, causing the glutamic acid (E) at amino acid position 13 to be replaced by an aspartic acid (D). 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

Oct 12, 2022

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 13 of the DNAH9 protein (p.Glu13Asp). This variant is present in population databases (rs186019513, gnomAD 0.1%). 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: 1464229). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Ciliary dyskinesia, primary, 40

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.68

CADD

Benign

7.7

DANN

Benign

0.55

DEOGEN2

Benign

0.0086

T;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.34

T;T;T

MetaRNN

Benign

0.0036

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.86

L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.40

N;.;N

REVEL

Benign

0.046

Sift

Benign

0.33

T;.;T

Sift4G

Pathogenic

0.0

.;D;.

Polyphen

0.0

B;.;B

Vest4

0.067

MutPred

0.19

Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);Gain of loop (P = 0.0435);

MVP

0.22

MPC

0.13

ClinPred

0.020

GERP RS

2.6

Varity_R

0.044

gMVP

0.27

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