rs1554294459

Variant names:

• chr7-21901174-A-ATCTGGACCTTCAGGCTGAAGAGCGAAGAGAGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCAT
• rs1554294459
• NM_001277115.2:c.13501_13502insGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCATTCTGGACCTTCAGGCTGAAGAGCGAAGAGA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001277115.2(DNAH11):​c.13501_13502insGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCATTCTGGACCTTCAGGCTGAAGAGCGAAGAGA​(p.Lys4501ArgfsTer17) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAH11 NM_001277115.2 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.60
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 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 6 pathogenic variants in the truncated region.
• PP5: Variant 7-21901174-A-ATCTGGACCTTCAGGCTGAAGAGCGAAGAGAGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCAT is Pathogenic according to our data. Variant chr7-21901174-A-ATCTGGACCTTCAGGCTGAAGAGCGAAGAGAGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCAT is described in ClinVar as Pathogenic. ClinVar VariationId is 238901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.13501_13502insGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCATTCTGGACCTTCAGGCTGAAGAGCGAAGAGA	p.Lys4501ArgfsTer17	frameshift_variant, stop_gained	Exon 82 of 82	ENST00000409508.8	NP_001264044.1
CDCA7L	NM_018719.5	c.*1147_*1148insATGGGAACAGTGCAGCAACATGCTAGAAAATCCTCACTGCACTCCAGCAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGCCAGAACCCATTTTGCAGTCCTCTCTTCGCTCTTCAGCCTGAAGGTCCAGA		3_prime_UTR_variant	Exon 10 of 10	ENST00000406877.8	NP_061189.2
CDCA7L	NM_001127370.3	c.*1147_*1148insATGGGAACAGTGCAGCAACATGCTAGAAAATCCTCACTGCACTCCAGCAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGCCAGAACCCATTTTGCAGTCCTCTCTTCGCTCTTCAGCCTGAAGGTCCAGA		3_prime_UTR_variant	Exon 11 of 11		NP_001120842.1
CDCA7L	NM_001127371.3	c.*1147_*1148insATGGGAACAGTGCAGCAACATGCTAGAAAATCCTCACTGCACTCCAGCAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGCCAGAACCCATTTTGCAGTCCTCTCTTCGCTCTTCAGCCTGAAGGTCCAGA		3_prime_UTR_variant	Exon 9 of 9		NP_001120843.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.13501_13502insGGACTGCAAAATGGGTTCTGGCTGGAGTGGCTCTGCTTCTAGAAGCGTAAGGTAACACTGGCATTCCTCTAGCCTCTGCTGGAGTGCAGTGAGGATTTTCTAGCATGTTGCTGCACTGTTCCCATTCTGGACCTTCAGGCTGAAGAGCGAAGAGA	p.Lys4501ArgfsTer17	frameshift_variant, stop_gained	Exon 82 of 82	5	NM_001277115.2	ENSP00000475939.1
CDCA7L	ENST00000406877.8	c.*1147_*1148insATGGGAACAGTGCAGCAACATGCTAGAAAATCCTCACTGCACTCCAGCAGAGGCTAGAGGAATGCCAGTGTTACCTTACGCTTCTAGAAGCAGAGCCACTCCAGCCAGAACCCATTTTGCAGTCCTCTCTTCGCTCTTCAGCCTGAAGGTCCAGA		3_prime_UTR_variant	Exon 10 of 10	1	NM_018719.5	ENSP00000383986.3

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

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Feb 17, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Lys4501Argfs*17) in the DNAH11 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the DNAH11 protein. This variant has not been reported in the literature in individuals with DNAH11-related conditions. ClinVar contains an entry for this variant (Variation ID: 238901). This variant disrupts the C-terminus of the DNAH11 protein. Other variant(s) that disrupt this region (p.Trp4505Serfs*10) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=84/16	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1554294459; hg19: chr7-21940792;