rs189432084

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001277115.2(DNAH11):ā€‹c.5132A>Gā€‹(p.Gln1711Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,600,310 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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‘“ 0.00032 ( 0 hom., cov: 31)
Exomes š‘“: 0.00046 ( 3 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 0.471
Variant links:
Genes affected
DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0073883235).
BP6
Variant 7-21658835-A-G is Benign according to our data. Variant chr7-21658835-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr7-21658835-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000462 (669/1448072) while in subpopulation MID AF= 0.0108 (62/5744). AF 95% confidence interval is 0.00864. There are 3 homozygotes in gnomad4_exome. There are 346 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DNAH11NM_001277115.2 linkuse as main transcriptc.5132A>G p.Gln1711Arg missense_variant 30/82 ENST00000409508.8 NP_001264044.1 Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DNAH11ENST00000409508.8 linkuse as main transcriptc.5132A>G p.Gln1711Arg missense_variant 30/825 NM_001277115.2 ENSP00000475939.1 Q96DT5

Frequencies

GnomAD3 genomes
AF:
0.000322
AC:
49
AN:
152120
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000394
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000500
Gnomad OTH
AF:
0.000955
GnomAD3 exomes
AF:
0.000531
AC:
121
AN:
228082
Hom.:
0
AF XY:
0.000577
AC XY:
71
AN XY:
122958
show subpopulations
Gnomad AFR exome
AF:
0.0000717
Gnomad AMR exome
AF:
0.000656
Gnomad ASJ exome
AF:
0.000838
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000325
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000714
Gnomad OTH exome
AF:
0.00160
GnomAD4 exome
AF:
0.000462
AC:
669
AN:
1448072
Hom.:
3
Cov.:
31
AF XY:
0.000481
AC XY:
346
AN XY:
718790
show subpopulations
Gnomad4 AFR exome
AF:
0.000601
Gnomad4 AMR exome
AF:
0.000800
Gnomad4 ASJ exome
AF:
0.000737
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000442
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000384
Gnomad4 OTH exome
AF:
0.00120
GnomAD4 genome
AF:
0.000322
AC:
49
AN:
152238
Hom.:
0
Cov.:
31
AF XY:
0.000269
AC XY:
20
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000393
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000500
Gnomad4 OTH
AF:
0.000945
Alfa
AF:
0.000622
Hom.:
1
Bravo
AF:
0.000378
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000975
AC:
8
ExAC
AF:
0.000606
AC:
73
Asia WGS
AF:
0.000577
AC:
2
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1Benign:2
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJan 12, 2015This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
DNAH11-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesDec 04, 2023The DNAH11 c.5132A>G variant is predicted to result in the amino acid substitution p.Gln1711Arg. This variant has been reported along with additional DNAH11 variants in individuals with primary ciliary dyskinesia (Table 4, Sherman et al. 2020. PubMed ID: 32662935; Alsamri et al. 2021. PubMed ID: 34768622). This variant is reported in 0.081% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMay 01, 2016- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 03, 2017p.Gln1711Arg in exon 30 of DNAH11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, shrew, tenrec, and platypus have an arginine (Arg) at this position desp ite high nearby amino acid conservation. In addition, computational prediction t ools do not suggest a high likelihood of impact to the protein. It has also been identified in 0.2% (48/26256) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs189432084). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.062
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
7.2
DANN
Benign
0.17
DEOGEN2
Benign
0.068
.;.;T
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.83
FATHMM_MKL
Benign
0.10
N
LIST_S2
Benign
0.69
T;T;T
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.0074
T;T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.31
T
PROVEAN
Benign
0.99
.;N;.
REVEL
Benign
0.072
Sift
Benign
1.0
.;T;.
Vest4
0.21
MVP
0.35
ClinPred
0.0080
T
GERP RS
2.4
Varity_R
0.091
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs189432084; hg19: chr7-21698453; API