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7-21901021-A-ACCCAAGCAGGAACCATTGTTGAAGCCCGTCT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_001277115.2(DNAH11):c.13320_13350dup(p.Lys4451ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T4440T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

DNAH11
NM_001277115.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: -0.590
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]
CDCA7L (HGNC:30777): (cell division cycle associated 7 like) Acts upstream of or within positive regulation of cell population proliferation. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 24 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-21901021-A-ACCCAAGCAGGAACCATTGTTGAAGCCCGTCT is Pathogenic according to our data. Variant chr7-21901021-A-ACCCAAGCAGGAACCATTGTTGAAGCCCGTCT is described in ClinVar as [Pathogenic]. Clinvar id is 1944204.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DNAH11NM_001277115.2 linkuse as main transcriptc.13320_13350dup p.Lys4451ProfsTer7 frameshift_variant 82/82 ENST00000409508.8
CDCA7LNM_018719.5 linkuse as main transcriptc.*1300_*1301insAGACGGGCTTCAACAATGGTTCCTGCTTGGG 3_prime_UTR_variant 10/10 ENST00000406877.8
CDCA7LNM_001127370.3 linkuse as main transcriptc.*1300_*1301insAGACGGGCTTCAACAATGGTTCCTGCTTGGG 3_prime_UTR_variant 11/11
CDCA7LNM_001127371.3 linkuse as main transcriptc.*1300_*1301insAGACGGGCTTCAACAATGGTTCCTGCTTGGG 3_prime_UTR_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DNAH11ENST00000409508.8 linkuse as main transcriptc.13320_13350dup p.Lys4451ProfsTer7 frameshift_variant 82/825 NM_001277115.2 P1
CDCA7LENST00000406877.8 linkuse as main transcriptc.*1300_*1301insAGACGGGCTTCAACAATGGTTCCTGCTTGGG 3_prime_UTR_variant 10/101 NM_018719.5 P1Q96GN5-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeSep 21, 2022For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the DNAH11 protein in which other variant(s) (p.Trp4505Serfs*10) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with DNAH11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys4451Profs*7) in the DNAH11 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the DNAH11 protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-21940639; API