rs117830543

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_001277115.2(DNAH11):c.3470T>G(p.Leu1157Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,613,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4

Conservation

PhyloP100: 7.53

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]

DNAH11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-21601440-T-G is Pathogenic according to our data. Variant chr7-21601440-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 359621.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=3, Pathogenic=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.26536918). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.3470T>G	p.Leu1157Arg	missense_variant	Exon 18 of 82	ENST00000409508.8	NP_001264044.1	Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8 link	c.3470T>G	p.Leu1157Arg	missense_variant	Exon 18 of 82	5	NM_001277115.2	ENSP00000475939.1		Q96DT5

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000125

AC:

AN:

248870

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135018

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00167

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461350

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00118

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 7

Pathogenic:2Uncertain:2

Feb 04, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2020

Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 12, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Leu1157Arg variant in DNAH11 has been reported in at least 4 individuals with primary ciliary dyskinesia (PMID: 32502479, 33942430, 31040315, 35518361), and has been identified in 0.12% (34/44870) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs117830543). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 359621) and has been interpreted as likely pathogenic by Beijing Children's Hospital, GeneDx, and Children‚Äôs Hospital of Fudan University, and a variant of uncertain significance by Illumina, Invitae, and PerkinElmer Genomics. Of the 4 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Leu1157Arg variant is pathogenic (Variation ID: 1012320; PMID: 33942430). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Leu1157Arg variant is uncertain. ACMG/AMP Criteria applied: PM3 (Richards 2015). -

Jul 07, 2020

Center for Molecular Medicine, Children’s Hospital of Fudan University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Pathogenic:1Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1157 of the DNAH11 protein (p.Leu1157Arg). This variant is present in population databases (rs117830543, gnomAD 0.2%). This missense change has been observed in individual(s) with DNAH11-related conditions and/or primary ciliary dyskinesia (PMID: 31040315, 32502479; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 359621). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DNAH11 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

May 31, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31040315, 33942430, 31507630, 32502479) -

not specified

Uncertain:1

Aug 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: DNAH11 c.3470T>G (p.Leu1157Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 248870 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in DNAH11 causing Primary Ciliary Dyskinesia 7, allowing no conclusion about variant significance. c.3470T>G has been reported in the literature in compound heteozygous individuals affected with Primary Ciliary Dyskinesia 7 (Guo_2020, Cao_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35441720, 32502479, 31040315, 34133440, 34405951, 35518361). ClinVar contains an entry for this variant (Variation ID: 359621). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Benign

-0.033

BayesDel_noAF

Pathogenic

0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

.;.;D

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.75

T;T;T

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.5

.;.;M

PrimateAI

Benign

0.48

PROVEAN

Pathogenic

-5.1

.;D;.

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

.;D;.

Polyphen

1.0

.;.;D

Vest4

0.85

MVP

0.42

ClinPred

0.49

GERP RS

5.7

Varity_R

0.39

gMVP

0.67

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