7-21892426-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001277115.2(DNAH11):c.12509C>T(p.Thr4170Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.412 in 1,604,288 control chromosomes in the GnomAD database, including 138,328 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T4170S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.38 ( 11341 hom., cov: 32)

Exomes 𝑓: 0.42 ( 126987 hom. )

Consequence

DNAH11
NM_001277115.2 missense, splice_region

Scores

Splicing: ADA: 0.00001818

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.49

Publications

30 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=0.0017268956).

BP6

Variant 7-21892426-C-T is Benign according to our data. Variant chr7-21892426-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

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.12509C>T	p.Thr4170Ile	missense splice_region	Exon 77 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.12509C>T	p.Thr4170Ile	missense splice_region	Exon 77 of 82	ENSP00000475939.1	Q96DT5
	DNAH11	ENST00000479878.1	TSL:3	n.-199C>T		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57426

AN:

151830

Hom.:

11334

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.493

Gnomad AMR

AF:

0.350

Gnomad ASJ

AF:

0.337

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.380

Gnomad FIN

AF:

0.473

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.373

GnomAD2 exomes

AF:

0.395

AC:

97209

AN:

246194

AF XY:

0.398

show subpopulations

Gnomad AFR exome

AF:

0.275

Gnomad AMR exome

AF:

0.297

Gnomad ASJ exome

AF:

0.348

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.476

Gnomad NFE exome

AF:

0.423

Gnomad OTH exome

AF:

0.406

GnomAD4 exome

AF:

0.415

AC:

603076

AN:

1452340

Hom.:

126987

Cov.:

AF XY:

0.415

AC XY:

298739

AN XY:

720636

show subpopulations

African (AFR)

AF:

0.270

AC:

9008

AN:

33302

American (AMR)

AF:

0.301

AC:

13357

AN:

44312

Ashkenazi Jewish (ASJ)

AF:

0.356

AC:

9205

AN:

25832

East Asian (EAS)

AF:

0.414

AC:

16337

AN:

39488

South Asian (SAS)

AF:

0.373

AC:

31973

AN:

85664

European-Finnish (FIN)

AF:

0.470

AC:

24997

AN:

53198

Middle Eastern (MID)

AF:

0.360

AC:

2058

AN:

5718

European-Non Finnish (NFE)

AF:

0.427

AC:

471743

AN:

1104918

Other (OTH)

AF:

0.407

AC:

24398

AN:

59908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

18395

36791

55186

73582

91977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14392

28784

43176

57568

71960

<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:

0.378

AC:

57470

AN:

151948

Hom.:

11341

Cov.:

AF XY:

0.380

AC XY:

28233

AN XY:

74264

show subpopulations

African (AFR)

AF:

0.282

AC:

11704

AN:

41454

American (AMR)

AF:

0.350

AC:

5330

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.337

AC:

1171

AN:

3470

East Asian (EAS)

AF:

0.462

AC:

2385

AN:

5158

South Asian (SAS)

AF:

0.381

AC:

1830

AN:

4804

European-Finnish (FIN)

AF:

0.473

AC:

4994

AN:

10552

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28701

AN:

67954

Other (OTH)

AF:

0.373

AC:

788

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1790

3580

5371

7161

8951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

568

1136

1704

2272

2840

<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:

0.405

Hom.:

58310

Bravo

AF:

0.363

TwinsUK

AF:

0.429

AC:

1591

ALSPAC

AF:

0.446

AC:

1719

ESP6500AA

AF:

0.271

AC:

1054

ESP6500EA

AF:

0.414

AC:

3433

ExAC

AF:

0.394

AC:

47616

Asia WGS

AF:

0.393

AC:

1369

AN:

3478

EpiCase

AF:

0.415

EpiControl

AF:

0.417

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

not provided (2)

Primary ciliary dyskinesia (2)

Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

7.9

(source)

DANN

Benign

0.66

DEOGEN2

Benign

0.015

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.039

LIST_S2

Benign

0.079

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.94

PhyloP100

1.5

PrimateAI

Benign

0.30

PROVEAN

Benign

2.2

REVEL

Benign

0.031

Sift

Benign

0.68

Vest4

0.027

ClinPred

0.0038

GERP RS

0.88

Varity_R

0.050

gMVP

0.098

Mutation Taster

=80/20

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000018

dbscSNV1_RF

Benign

0.0040

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over