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):ā€‹c.42C>Gā€‹(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: š‘“ 0.0018 ( 0 hom., cov: 31)
Exomes š‘“: 0.00016 ( 0 hom. )

Consequence

DNAH9
NM_001372.4 missense

Scores

1
1
16

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]

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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
DNAH9NM_001372.4 linkuse as main transcriptc.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
DNAH9ENST00000262442.9 linkuse as main transcriptc.42C>G p.Asn14Lys missense_variant 1/691 NM_001372.4 ENSP00000262442 P1Q9NYC9-1
DNAH9ENST00000579406.1 linkuse as main transcriptn.69C>G non_coding_transcript_exon_variant 1/81
DNAH9ENST00000454412.6 linkuse as main transcriptc.42C>G p.Asn14Lys missense_variant 1/685 ENSP00000414874
DNAH9ENST00000579828.5 linkuse as main transcriptc.42C>G p.Asn14Lys missense_variant 1/42 ENSP00000463782

Frequencies

GnomAD3 genomes
AF:
0.00177
AC:
259
AN:
146632
Hom.:
0
Cov.:
31
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:
9
AN:
30774
Hom.:
0
AF XY:
0.000279
AC XY:
5
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.:
0
Cov.:
33
AF XY:
0.000155
AC XY:
95
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.:
0
Cov.:
31
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.:
0
Bravo
AF:
0.00213
ExAC
AF:
0.000311
AC:
25
Asia WGS
AF:
0.000578
AC:
2
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 20, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 26, 2023In 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 submitterclinical testingAmbry GeneticsApr 25, 2023The 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 providedclinical testingPreventionGenetics, part of Exact SciencesJul 31, 2019This 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
T
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
N
LIST_S2
Benign
0.52
T;T;T
MetaRNN
Benign
0.0051
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.40
N;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Pathogenic
0.80
D
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
T
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.

Other links and lift over

dbSNP: rs377715895; hg19: chr17-11501857; API