rs727502977

chr5-13919318-GC-G

Variant summary

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

The NM_001369.3(DNAH5):c.832del(p.Ala278ArgfsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000434 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A278A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: DNAH5 NM_001369.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.05

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 5-13919318-GC-G is Pathogenic according to our data. Variant chr5-13919318-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 163160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.832del	p.Ala278ArgfsTer27	frameshift_variant	7/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.832del	p.Ala278ArgfsTer27	frameshift_variant	7/79	1	NM_001369.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461792 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727194

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74306

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:4

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2018	The c.832delG pathogenic mutation, located in coding exon 7 of the DNAH5 gene, results from a deletion of one nucleotide at nucleotide position 832, causing a translational frameshift with a predicted alternate stop codon (p.A278Rfs*27). This mutation has been reported in multiple individuals with primary ciliary dyskinesia in conjunction with a second DNAH5 alteration (Hornef N et al. Am. J. Respir. Crit. Care Med., 2006 Jul;174:120-6; Davis SD et al. Am. J. Respir. Crit. Care Med., 2018 Aug; doi: 10.1164/rccm.201803-0548OC). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Ala278Argfs*27) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 163160). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 08, 2013	The Ala278fs variant in DNAH5 has been reported in one individual with PCD and o uter dynein arm (ODA) defects who carried a nonsense variant identified on the o ther copy of this gene (Hornef 2006). The variant has not been identified in lar ge population studies. This frameshift variant is predicted to alter the protein 's amino acid sequence beginning at position 278 and lead to a premature termina tion codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in DN AH5 are associated with autosomal recessive PCD (Hornef 2006). In summary, this variant is likely pathogenic, though additional studies are required to fully es tablish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs727502977; hg19: chr5-13919427;