rs35865357

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001277115.2(DNAH11):c.8990G>A(p.Arg2997Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0165 in 1,613,800 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2997W) has been classified as Benign.

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 31)

Exomes 𝑓: 0.017 ( 260 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.49

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009184986).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1720/152198) while in subpopulation NFE AF= 0.0184 (1254/68006). AF 95% confidence interval is 0.0176. There are 17 homozygotes in gnomad4. There are 820 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.8990G>A	p.Arg2997Gln	missense_variant	55/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8 linkuse as main transcript	c.8990G>A	p.Arg2997Gln	missense_variant	55/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1719

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00360

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00970

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00685

Gnomad FIN

AF:

0.00650

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0184

Gnomad OTH

AF:

0.00958

GnomAD3 exomes

AF:

0.0112

AC:

2798

AN:

249018

Hom.:

AF XY:

0.0111

AC XY:

1497

AN XY:

135084

show subpopulations

Gnomad AFR exome

AF:

0.00400

Gnomad AMR exome

AF:

0.00684

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.00605

Gnomad FIN exome

AF:

0.00650

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0170

AC:

24886

AN:

1461602

Hom.:

260

Cov.:

AF XY:

0.0166

AC XY:

12042

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00305

Gnomad4 AMR exome

AF:

0.00715

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00576

Gnomad4 FIN exome

AF:

0.00751

Gnomad4 NFE exome

AF:

0.0201

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0113

AC:

1720

AN:

152198

Hom.:

Cov.:

AF XY:

0.0110

AC XY:

820

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00359

Gnomad4 AMR

AF:

0.00969

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00707

Gnomad4 FIN

AF:

0.00650

Gnomad4 NFE

AF:

0.0184

Gnomad4 OTH

AF:

0.00948

Alfa

AF:

0.0153

Hom.:

Bravo

AF:

0.0110

TwinsUK

AF:

0.0218

AC:

ALSPAC

AF:

0.0197

AC:

ESP6500AA

AF:

0.00445

AC:

ESP6500EA

AF:

0.0186

AC:

156

ExAC

AF:

0.0109

AC:

1321

Asia WGS

AF:

0.00115

AC:

AN:

3476

EpiCase

AF:

0.0161

EpiControl

AF:

0.0151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg2997Gln in exon 55 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 1.9% (156/8366) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs35865357). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2021	This variant is associated with the following publications: (PMID: 31213628, 24450482, 12142464) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	DNAH11: BP4, BS1, BS2 -

Primary ciliary dyskinesia 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Oct 01, 2021

PM1, PP3, PP5, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.0092

T;T;T

MetaSVM

Benign

-0.46

MutationTaster

Benign

1.0

PrimateAI

Benign

0.35

Vest4

0.18

ClinPred

0.046

GERP RS

5.8

Varity_R

0.64

gMVP

0.53

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