7-21543303-C-A

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.58C>A(p.Arg20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000973 in 1,549,134 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. R20C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0019 ( 4 hom., cov: 33)

Exomes 𝑓: 0.00088 ( 14 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.343

Publications

4 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=0.0040258765).

BP6

Variant 7-21543303-C-A is Benign according to our data. Variant chr7-21543303-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 218583.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00187 (285/152310) while in subpopulation AMR AF = 0.0161 (247/15308). AF 95% confidence interval is 0.0145. There are 4 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AR,AD 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.58C>A	p.Arg20Ser	missense	Exon 1 of 82	NP_001264044.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.58C>A	p.Arg20Ser	missense	Exon 1 of 82	ENSP00000475939.1
	DNAH11	ENST00000607050.1	TSL:3	n.-143C>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes

AF:

0.00187

AC:

285

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0162

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000970

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00549

AC:

826

AN:

150532

AF XY:

0.00408

show subpopulations

Gnomad AFR exome

AF:

0.000278

Gnomad AMR exome

AF:

0.0318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00242

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000694

Gnomad OTH exome

AF:

0.00304

GnomAD4 exome

AF:

0.000876

AC:

1223

AN:

1396824

Hom.:

Cov.:

AF XY:

0.000757

AC XY:

521

AN XY:

688692

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

31542

American (AMR)

AF:

0.0290

AC:

1033

AN:

35656

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25148

East Asian (EAS)

AF:

0.00328

AC:

117

AN:

35706

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5050

European-Non Finnish (NFE)

AF:

0.0000167

AC:

AN:

1078112

Other (OTH)

AF:

0.000829

AC:

AN:

57884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00187

AC:

285

AN:

152310

Hom.:

Cov.:

AF XY:

0.00236

AC XY:

176

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

41584

American (AMR)

AF:

0.0161

AC:

247

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000972

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00236

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

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:

0.000698

Hom.:

Bravo

AF:

0.00331

ExAC

AF:

0.000451

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.65

CADD

Benign

9.5

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PhyloP100

-0.34

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.11

Sift

Benign

0.095

Polyphen

0.093

Vest4

0.20

MVP

0.085

ClinPred

0.017

GERP RS

-0.63

PromoterAI

0.015

Neutral

(source)

Varity_R

0.36

gMVP

0.43

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over