Genetic Variant DNAH11:p.Cys227Phe (chr7-21558986-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001277115.2(DNAH11):c.680G>T(p.Cys227Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. 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. C227S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.120

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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.052916616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.680G>T	p.Cys227Phe	missense_variant	Exon 3 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8 link	c.680G>T	p.Cys227Phe	missense_variant	Exon 3 of 82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1425758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

705442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32770

American (AMR)

AF:

0.00

AC:

AN:

39196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25408

East Asian (EAS)

AF:

0.00

AC:

AN:

38302

South Asian (SAS)

AF:

0.00

AC:

AN:

81312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51454

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.15e-7

AC:

AN:

1092456

Other (OTH)

AF:

0.00

AC:

AN:

59138

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

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.33

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.0

.;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.52

T;T;T

M_CAP

Benign

0.0020

MetaRNN

Benign

0.053

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;N

PhyloP100

-0.12

PrimateAI

Benign

0.31

PROVEAN

Benign

0.0

.;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;.

Sift4G

Pathogenic

0.0

.;.;.

Vest4

0.25

ClinPred

0.10

GERP RS

-3.5

Varity_R

0.054

gMVP

0.087

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over