rs1554049087

chr5-13788755-ATG-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001369.3(DNAH5):c.8606_8607del(p.Thr2869IlefsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. T2869T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DNAH5 NM_001369.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.09

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 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-13788755-ATG-A is Pathogenic according to our data. Variant chr5-13788755-ATG-A is described in ClinVar as [Pathogenic]. Clinvar id is 454810.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.8606_8607del	p.Thr2869IlefsTer11	frameshift_variant	51/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.8606_8607del	p.Thr2869IlefsTer11	frameshift_variant	51/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.8561_8562del	p.Thr2854IlefsTer11	frameshift_variant	51/79			A1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 05, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 454810). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Thr2869Ilefs*11) 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). -

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: rs1554049087; hg19: chr5-13788864;