17-11598540-C-G

Position:

chr17-11598540-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_001372.4(DNAH9):c.42C>G(p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000327 in 1,402,268 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

DNAH9
NM_001372.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: -0.735

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 Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0050899684).

BP6

Variant 17-11598540-C-G is Benign according to our data. Variant chr17-11598540-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1570552.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00177 (260/146746) while in subpopulation AFR AF= 0.0059 (243/41204). AF 95% confidence interval is 0.00529. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH9	NM_001372.4 linkuse as main transcript	c.42C>G	p.Asn14Lys	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.42C>G	p.Asn14Lys	missense_variant	1/69	1	NM_001372.4	ENSP00000262442	P1	Q9NYC9-1
DNAH9	ENST00000579406.1 linkuse as main transcript	n.69C>G		non_coding_transcript_exon_variant	1/8	1
DNAH9	ENST00000454412.6 linkuse as main transcript	c.42C>G	p.Asn14Lys	missense_variant	1/68	5		ENSP00000414874
DNAH9	ENST00000579828.5 linkuse as main transcript	c.42C>G	p.Asn14Lys	missense_variant	1/4	2		ENSP00000463782

Frequencies

GnomAD3 genomes

AF:

0.00177

AC:

259

AN:

146632

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00589

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000887

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00149

GnomAD3 exomes

AF:

0.000292

AC:

AN:

30774

Hom.:

AF XY:

0.000279

AC XY:

AN XY:

17928

show subpopulations

Gnomad AFR exome

AF:

0.00884

Gnomad AMR exome

AF:

0.000331

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000159

AC:

199

AN:

1255522

Hom.:

Cov.:

AF XY:

0.000155

AC XY:

AN XY:

613442

show subpopulations

Gnomad4 AFR exome

AF:

0.00663

Gnomad4 AMR exome

AF:

0.000436

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:

0.00000392

Gnomad4 OTH exome

AF:

0.000386

GnomAD4 genome

AF:

0.00177

AC:

260

AN:

146746

Hom.:

Cov.:

AF XY:

0.00162

AC XY:

116

AN XY:

71574

show subpopulations

Gnomad4 AFR

AF:

0.00590

Gnomad4 AMR

AF:

0.000886

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00147

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00213

ExAC

AF:

0.000311

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2023

The c.42C>G (p.N14K) 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 42, causing the asparagine (N) at amino acid position 14 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DNAH9-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.55

DANN

Benign

0.45

DEOGEN2

Benign

0.0037

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.074

LIST_S2

Benign

0.52

T;T;T

MetaRNN

Benign

0.0051

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.40

N;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-0.48

N;.;N

REVEL

Benign

0.015

Sift

Benign

0.79

T;.;T

Sift4G

Uncertain

0.036

.;D;.

Polyphen

0.0

B;.;B

Vest4

0.10

MutPred

0.28

Gain of ubiquitination at N14 (P = 0.0029);Gain of ubiquitination at N14 (P = 0.0029);Gain of ubiquitination at N14 (P = 0.0029);

MVP

0.13

MPC

0.11

ClinPred

0.0037

GERP RS

-0.63

Varity_R

0.032

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