Genetic Variant DNAH11:p.Met1? (chr7-21543246-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_001277115.2(DNAH11):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000725 in 1,380,104 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

DNAH11
NM_001277115.2 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.102

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: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 13 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 21543447. Lost 0.015 part of the original CDS.

PS1

Another start lost variant in NM_001277115.2 (DNAH11) was described as [Likely_pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 82	ENST00000409508.8	NP_001264044.1	Q96DT5Q96NT7H9NAJ8H9NAJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 82	5	NM_001277115.2	ENSP00000475939.1		Q96DT5
DNAH11	ENST00000607050.1 link	n.-200A>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.25e-7

AC:

AN:

1380104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

678936

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31062

American (AMR)

AF:

0.00

AC:

AN:

34280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24760

East Asian (EAS)

AF:

0.00

AC:

AN:

35428

South Asian (SAS)

AF:

0.00

AC:

AN:

78282

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4074

European-Non Finnish (NFE)

AF:

9.34e-7

AC:

AN:

1071056

Other (OTH)

AF:

0.00

AC:

AN:

57106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.028

.;.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.25

LIST_S2

Uncertain

0.90

D;D;D

M_CAP

Benign

0.059

MetaRNN

Uncertain

0.42

T;T;T

MetaSVM

Benign

-1.1

PhyloP100

0.10

PROVEAN

Benign

-0.39

.;N;.

REVEL

Uncertain

0.31

Sift

Pathogenic

0.0

.;D;.

Polyphen

0.0

.;.;B

Vest4

0.51

MutPred

0.66

Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);

MVP

0.17

ClinPred

0.53

GERP RS

2.3

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.32

gMVP

0.18

Mutation Taster

=67/133

disease causing

(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