rs1178187217

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001277115.2(DNAH11):c.2966G>A(p.Arg989Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000447 in 1,566,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 6.08

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.917

PP5

Variant 7-21600085-G-A is Pathogenic according to our data. Variant chr7-21600085-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453287.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr7-21600085-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.2966G>A	p.Arg989Gln	missense_variant	15/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8 linkuse as main transcript	c.2966G>A	p.Arg989Gln	missense_variant	15/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000353

AC:

AN:

1414544

Hom.:

Cov.:

AF XY:

0.00000429

AC XY:

AN XY:

698714

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:

0.0000389

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000184

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Dec 11, 2023	This sequence change replaces arginine (basic and polar) with glutamine (charge-neutral and polar) at codon 989 of the DNAH11 protein (p.Arg989Gln). The variant c.2966G>A has a low allele frequency in gnomAD Genomes (Version 3.1.2: ƒ = 0.000013). Particular in silico pathogenicity prediction tools (MetaRNN, MutPred, DANN, EIGEN PC, Mutation assessor, etc) predicted the c.2966G>A to be likely deleterious. ClinVar contains an entry for this variant (records with likely pathogenic and VUS interpretations (variation ID 453287)). The patient possessed the c.2966G>A variant in trans with another rare missense variant in DNAH11 (c.2824C>A, p.Pro942Thr). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Apr 29, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 989 of the DNAH11 protein (p.Arg989Gln). This variant is present in population databases (no rsID available, gnomAD 0.0008%). This variant has not been reported in the literature in individuals affected with DNAH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 453287). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH11 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. -

Primary ciliary dyskinesia 7

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Jul 30, 2019

For this patient, the lab reported the c.6727C>T (p.R2243X) variant as pathogenic and the c.2966G>A (p.R989Q) as a VUS. We sent a nasal biopsy for ciliary beat frequency analysis and the results came back inconclusive, but the beating pattern was analogous to other DNAH11 mutation beating patterns. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

.;.;T

Eigen

Uncertain

0.68

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.92

D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Pathogenic

3.2

.;.;M

MutationTaster

Benign

1.0

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.3

.;D;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

.;D;.

Polyphen

1.0

.;.;D

Vest4

0.55

MutPred

0.76

Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);Loss of MoRF binding (P = 0.025);

MVP

0.47

ClinPred

0.99

GERP RS

5.5

Varity_R

0.31

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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