Genetic Variant DNAH11:p.Lys3687Gln (chr7-21852629-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001277115.2(DNAH11):c.11059A>C(p.Lys3687Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000699 in 1,430,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3687E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense, splice_region

Scores

Splicing: ADA: 0.0009512

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.24

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3683169).

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.11059A>C	p.Lys3687Gln	missense splice_region	Exon 67 of 82	NP_001264044.1	Q96DT5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DNAH11	ENST00000409508.8	TSL:5 MANE Select	c.11059A>C	p.Lys3687Gln	missense splice_region	Exon 67 of 82	ENSP00000475939.1	Q96DT5
DNAH11	ENST00000421290.1	TSL:4	n.242A>C		splice_region non_coding_transcript_exon	Exon 2 of 4
DNAH11	ENST00000607413.5	TSL:4	n.322A>C		splice_region non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709134

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32122

American (AMR)

AF:

0.00

AC:

AN:

38720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24254

East Asian (EAS)

AF:

0.00

AC:

AN:

39402

South Asian (SAS)

AF:

0.00

AC:

AN:

79952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5562

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098894

Other (OTH)

AF:

0.0000169

AC:

AN:

59000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.061

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.81

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.018

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.87

PhyloP100

5.2

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.31

Sift

Benign

0.059

Vest4

0.37

MutPred

0.38

Loss of ubiquitination at K3694 (P = 0.0087)

MVP

0.63

ClinPred

0.99

GERP RS

3.7

Varity_R

0.43

gMVP

0.56

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00095

dbscSNV1_RF

Benign

0.054

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over