rs797045086

Variant names:

• chr7-21735706-G-GGTT
• rs797045086
• NM_001277115.2:c.7508_7509insTTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001277115.2(DNAH11):​c.7508_7509insTTG​(p.Gly2503_Lys2504insTer) variant causes a stop gained, disruptive inframe insertion change. The variant allele was found at a frequency of 0.000000684 in 1,461,518 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 stop_gained, disruptive_inframe_insertion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-21735706-G-GGTT is Pathogenic according to our data. Variant chr7-21735706-G-GGTT is described in ClinVar as [Pathogenic]. Clinvar id is 208573.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.7508_7509insTTG	p.Gly2503_Lys2504insTer	stop_gained, disruptive_inframe_insertion	Exon 46 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.7508_7509insTTG	p.Gly2503_Lys2504insTer	stop_gained, disruptive_inframe_insertion	Exon 46 of 82	5	NM_001277115.2	ENSP00000475939.1
DNAH11	ENST00000605912.1	c.68_69insTTG	p.Gly23_Lys24insTer	stop_gained, disruptive_inframe_insertion	Exon 1 of 4	3		ENSP00000476068.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 7 Pathogenic:2

Feb 14, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Gly2504Ter variant in DNAH11 has not been previously reported in the literature in individuals with primary ciliary dyskinesia, but has been identified iin 0.002% (1/62478) of remaining chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797045086). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 208573) and has been interpreted as pathogenic by Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine). This nonsense variant leads to a premature termination codon at position 2504, which is predicted to lead to a truncated or absent protein. Loss of function of the DNAH11 gene is an established disease mechanism in autosomal recessive primary ciliary dyskinesia. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive primary ciliary dyskinesia. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015). -

Jan 21, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys2504X variant in DNAH11 has not been previously reported in individuals with primary ciliary dyskinesia (PCD) and was absent from large population studies. This variant is an insertion of 3 bases and introduces a nonsense variant which leads to a premature termination codon at position 2504. This variant is predicted to lead to a truncated or absent protein. Complete loss of DNAH11 function is an established disease mechanism in PCD. In summary, this variant meets our criteria to be classified as pathogenic for PCD in an autosomal recessive manner based on the predicted impact of the variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045086; hg19: chr7-21775324;