rs68023059

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001277115.2(DNAH11):c.7552G>A(p.Val2518Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0358 in 1,613,926 control chromosomes in the GnomAD database, including 1,244 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2518A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.026 ( 73 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1171 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.40

Publications

14 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: Labcorp Genetics (formerly Invitae), ClinGen, Laboratory for Molecular Medicine
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003411591).

BP6

Variant 7-21735751-G-A is Benign according to our data. Variant chr7-21735751-G-A is described in ClinVar as Benign. ClinVar VariationId is 163108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0256 (3900/152268) while in subpopulation NFE AF = 0.0412 (2803/68022). AF 95% confidence interval is 0.0399. There are 73 homozygotes in GnomAd4. There are 1781 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 73 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001277115.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	NM_001277115.2	MANE Select	c.7552G>A	p.Val2518Ile	missense	Exon 46 of 82	NP_001264044.1	Q96DT5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.7552G>A	p.Val2518Ile	missense	Exon 46 of 82	ENSP00000475939.1	Q96DT5
	DNAH11	ENST00000605912.1	TSL:3	c.112G>A	p.Val38Ile	missense	Exon 1 of 4	ENSP00000476068.1	U3KQN2

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

3900

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00760

Gnomad AMI

AF:

0.0537

Gnomad AMR

AF:

0.0243

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0193

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0412

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0269

AC:

6695

AN:

249220

AF XY:

0.0269

show subpopulations

Gnomad AFR exome

AF:

0.00588

Gnomad AMR exome

AF:

0.0166

Gnomad ASJ exome

AF:

0.0245

Gnomad EAS exome

AF:

0.000111

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.0445

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0369

AC:

53881

AN:

1461658

Hom.:

1171

Cov.:

AF XY:

0.0358

AC XY:

26055

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00544

AC:

182

AN:

33480

American (AMR)

AF:

0.0167

AC:

746

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

640

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00547

AC:

472

AN:

86256

European-Finnish (FIN)

AF:

0.0220

AC:

1174

AN:

53402

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0438

AC:

48726

AN:

1111830

Other (OTH)

AF:

0.0308

AC:

1857

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2787

5574

8362

11149

13936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1770

3540

5310

7080

8850

<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:

0.0256

AC:

3900

AN:

152268

Hom.:

Cov.:

AF XY:

0.0239

AC XY:

1781

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00758

AC:

315

AN:

41564

American (AMR)

AF:

0.0243

AC:

371

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00477

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0193

AC:

205

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0412

AC:

2803

AN:

68022

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

187

374

562

749

936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<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:

0.0355

Hom.:

261

Bravo

AF:

0.0256

TwinsUK

AF:

0.0426

AC:

158

ALSPAC

AF:

0.0428

AC:

165

ESP6500AA

AF:

0.00652

AC:

ESP6500EA

AF:

0.0416

AC:

344

ExAC

AF:

0.0284

AC:

3434

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0437

EpiControl

AF:

0.0429

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.092

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.0034

MetaSVM

Benign

-1.1

PhyloP100

3.4

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.80

REVEL

Benign

0.044

Sift

Benign

0.19

Sift4G

Benign

0.35

Vest4

0.13

ClinPred

0.0058

GERP RS

2.2

PromoterAI

0.019

Neutral

(source)

Varity_R

0.056

gMVP

0.17

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over