rs72657389

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001277115.2(DNAH11):c.9935A>T(p.Asp3312Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,569,876 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D3312D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 11 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.70

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 7
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0102032125).

BP6

Variant 7-21789251-A-T is Benign according to our data. Variant chr7-21789251-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163118.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00312 (475/152208) while in subpopulation NFE AF = 0.00413 (281/68002). AF 95% confidence interval is 0.00374. There are 3 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.9935A>T	p.Asp3312Val	missense_variant	Exon 61 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.9935A>T	p.Asp3312Val	missense_variant	Exon 61 of 82	5	NM_001277115.2	ENSP00000475939.1		Q96DT5

Frequencies

GnomAD3 genomes

AF:

0.00313

AC:

476

AN:

152090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00829

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00413

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00362

AC:

672

AN:

185544

AF XY:

0.00344

show subpopulations

Gnomad AFR exome

AF:

0.000756

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.000336

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00891

Gnomad NFE exome

AF:

0.00360

Gnomad OTH exome

AF:

0.00811

GnomAD4 exome

AF:

0.00330

AC:

4684

AN:

1417668

Hom.:

Cov.:

AF XY:

0.00328

AC XY:

2298

AN XY:

700770

show subpopulations

African (AFR)

AF:

0.000494

AC:

AN:

32416

American (AMR)

AF:

0.00401

AC:

153

AN:

38136

Ashkenazi Jewish (ASJ)

AF:

0.000355

AC:

AN:

25344

East Asian (EAS)

AF:

0.00

AC:

AN:

37518

South Asian (SAS)

AF:

0.00258

AC:

207

AN:

80156

European-Finnish (FIN)

AF:

0.00818

AC:

415

AN:

50758

Middle Eastern (MID)

AF:

0.00384

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00337

AC:

3671

AN:

1088780

Other (OTH)

AF:

0.00325

AC:

191

AN:

58838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

213

425

638

850

1063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

252

378

504

630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00312

AC:

475

AN:

152208

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

256

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000698

AC:

AN:

41538

American (AMR)

AF:

0.00373

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00207

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00829

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00413

AC:

281

AN:

68002

Other (OTH)

AF:

0.00379

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.00250

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000264

AC:

ESP6500EA

AF:

0.00402

AC:

ExAC

AF:

0.00255

AC:

304

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has been previously reported as a likely benign and benign variant (PMID: 30819905, 22184204); 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: 22184204, 33111339, 30819905) -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH11: BP4, BS2 -

not specified

Benign:2

Sep 30, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Asp3312Val in exon 61 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 0.7% (88/12864) of European chro mosomes, including 1 homozygote by the Exome Aggregation Consortium (ExAC, http: //exac.broadinstitute.org; dbSNP rs72657389). -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 7

Benign:2

Oct 21, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Primary ciliary dyskinesia

Benign:1

Dec 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.50

.;.;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Uncertain

-0.27

PhyloP100

8.7

PrimateAI

Benign

0.46

PROVEAN

Pathogenic

-7.4

.;D;.

REVEL

Uncertain

0.54

Sift

Benign

0.29

.;T;.

Vest4

0.53

MVP

0.80

ClinPred

0.082

GERP RS

6.2

Varity_R

0.58

gMVP

0.49

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over