rs182389910

Positions:

Variant summary

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

The NM_001277115.2(DNAH11):c.11233G>A(p.Glu3745Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,246 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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 0.0044 ( 16 hom., cov: 33)

Exomes 𝑓: 0.0027 ( 36 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 1.12

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005862832).

BP6

Variant 7-21861883-G-A is Benign according to our data. Variant chr7-21861883-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226579.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=5}. Variant chr7-21861883-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00438 (666/152140) while in subpopulation AMR AF= 0.0308 (471/15282). AF 95% confidence interval is 0.0285. There are 16 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.11233G>A	p.Glu3745Lys	missense_variant	69/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH11	ENST00000409508.8 linkuse as main transcript	c.11233G>A	p.Glu3745Lys	missense_variant	69/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1 linkuse as main transcript	n.416G>A		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5 linkuse as main transcript	n.496G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes

AF:

0.00438

AC:

666

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000846

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00198

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00190

Gnomad OTH

AF:

0.00479

GnomAD3 exomes

AF:

0.00569

AC:

1410

AN:

247996

Hom.:

AF XY:

0.00467

AC XY:

629

AN XY:

134564

show subpopulations

Gnomad AFR exome

AF:

0.000453

Gnomad AMR exome

AF:

0.0323

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000459

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00160

Gnomad OTH exome

AF:

0.00617

GnomAD4 exome

AF:

0.00266

AC:

3891

AN:

1461106

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1753

AN XY:

726832

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.0305

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000383

Gnomad4 FIN exome

AF:

0.00347

Gnomad4 NFE exome

AF:

0.00194

Gnomad4 OTH exome

AF:

0.00227

GnomAD4 genome

AF:

0.00438

AC:

666

AN:

152140

Hom.:

Cov.:

AF XY:

0.00527

AC XY:

392

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000843

Gnomad4 AMR

AF:

0.0308

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00198

Gnomad4 NFE

AF:

0.00190

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00131

Hom.:

Bravo

AF:

0.00576

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000246

AC:

ESP6500EA

AF:

0.00227

AC:

ExAC

AF:

0.00422

AC:

511

EpiCase

AF:

0.00158

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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 submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2015

p.Glu3745Lys in exon 69 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 3.0% (360/11530), including 10 h omozygotes, of Latino chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs182389910). -

Primary ciliary dyskinesia 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.13

.;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.66

T;T;T

MetaRNN

Benign

0.0059

T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.5

.;N;.

REVEL

Benign

0.11

Sift

Benign

0.47

.;T;.

Vest4

0.46

MVP

0.38

ClinPred

0.017

GERP RS

-0.00051

Varity_R

0.056

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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