rs575775297

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001277115.2(DNAH11):c.3288G>A(p.Met1096Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000156 in 1,611,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 0.913

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: 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01777324).

BP6

Variant 7-21601042-G-A is Benign according to our data. Variant chr7-21601042-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238908.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000147 (214/1459674) while in subpopulation MID AF = 0.0066 (38/5756). AF 95% confidence interval is 0.00494. There are 0 homozygotes in GnomAdExome4. There are 99 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check.

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.3288G>A	p.Met1096Ile	missense	Exon 17 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.3288G>A	p.Met1096Ile	missense	Exon 17 of 82	ENSP00000475939.1	Q96DT5

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000166

AC:

AN:

246520

AF XY:

0.000180

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000295

Gnomad ASJ exome

AF:

0.0000999

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000249

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000147

AC:

214

AN:

1459674

Hom.:

Cov.:

AF XY:

0.000136

AC XY:

AN XY:

725950

show subpopulations

African (AFR)

AF:

0.000180

AC:

AN:

33318

American (AMR)

AF:

0.000362

AC:

AN:

44232

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00660

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000121

AC:

134

AN:

1111514

Other (OTH)

AF:

0.000299

AC:

AN:

60300

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000250

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41570

American (AMR)

AF:

0.00137

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68018

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000213

Hom.:

Bravo

AF:

0.000434

ExAC

AF:

0.000166

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Primary ciliary dyskinesia (2)

not provided (1)

Primary ciliary dyskinesia 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.022

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.22

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

M_CAP

Benign

0.0064

MetaRNN

Benign

0.018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.51

PhyloP100

0.91

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.28

REVEL

Benign

0.10

Sift

Benign

0.80

Polyphen

0.0010

Vest4

0.27

MutPred

0.43

Loss of ubiquitination at K1098 (P = 0.1069)

MVP

0.15

ClinPred

0.020

GERP RS

4.5

Varity_R

0.55

gMVP

0.26

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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