rs727504802

Positions:

• chr5-13770904-GC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000265104.5(DNAH5):​c.9449del​(p.Gly3150AlafsTer24) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G3150G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DNAH5 ENST00000265104.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.11

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 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 5-13770904-GC-G is Pathogenic according to our data. Variant chr5-13770904-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.9449del	p.Gly3150AlafsTer24	frameshift_variant	56/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.9449del	p.Gly3150AlafsTer24	frameshift_variant	56/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1	c.9404del	p.Gly3135AlafsTer24	frameshift_variant	56/79			ENSP00000505288	A1
DNAH5	ENST00000504001.3	n.161del		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 08, 2013	The Gly3150fs variant in DNAH5 has not been previously identified in individuals with pulmonary disease nor has it been identified in large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 3150 and lead to a premature termination codon 24 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Frameshift and other truncating variants in DNAH5 are associated wit h autosomal recessive primary ciliary dyskinesia (PCD) with outer dynein arm (OD A) defects (Olbrich 2002, Hornef 2006, Ferkol 2013). In summary, this variant is likely pathogenic, though additional studies are required to fully establish it s clinical significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 02, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 179339). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly3150Alafs*24) in the DNAH5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DNAH5 are known to be pathogenic (PMID: 11788826, 16627867). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 23, 2015

The c.9449delG deletion in the DNAH5 gene has been reported previously in an individual with confirmed PCD who harbored this variant in the heterozygous state, without a second identifiable variant in this gene; sequence analysis of 11 other PCD related genes in this individual was negative (Kim et al., 2014). The c.9449delG variant causes a frameshift starting with codon Glycine 3150, changes this amino acid to a Alanine residue, and creates a premature Stop codon at position 24 of the new reading frame, denoted p.Gly3150AlafsX24. This deletion is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Frameshift and other protein truncating variantsdownstream of this deletion have been reported in the Human Gene Mutation Database in association with PCD (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. The c.9449delG deletion was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.9449delG as a pathogenic variant. -

DNAH5-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2024

The DNAH5 c.9449delG variant is predicted to result in a frameshift and premature protein termination (p.Gly3150Alafs*24). This variant was reported in an individual with primary ciliary dyskinesia (PCD) as the only detected DNAH5 variant, while testing of other PCD related genes was negative (Kim et al 2014. PubMed ID: 24498942). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in DNAH5 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504802; hg19: chr5-13771013;