rs542708170

Positions:

• chr5-13864632-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001369.3(DNAH5):​c.4361G>A​(p.Arg1454Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,614,038 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U: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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902
• PP5: Variant 5-13864632-C-T is Pathogenic according to our data. Variant chr5-13864632-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 287698.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.4361G>A	p.Arg1454Gln	missense_variant	28/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.4361G>A	p.Arg1454Gln	missense_variant	28/79	1	NM_001369.3	P4
	ENST00000503244.2	n.253+4077C>T		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1	c.4316G>A	p.Arg1439Gln	missense_variant	28/79			A1
	ENST00000637153.1	n.213+4117C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000836 AC: 21 AN: 251286 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135800

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000142 AC: 207 AN: 1461838 Hom.: 0 Cov.: 33 AF XY: 0.000136 AC XY: 99 AN XY: 727226

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74406

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000136

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1454 of the DNAH5 protein (p.Arg1454Gln). This variant is present in population databases (rs542708170, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 11788826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 287698). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH5 protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Feb 05, 2024	This sequence change in DNAH5 is predicted to replace arginine with glutamine at codon 1454, p.(Arg1454Gln). The arginine residue is moderately conserved (100 vertebrates, Multiz Alignments), and is located in the coiled-coiled stem region. There is a small physicochemical difference between arginine and glutamine. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.02% (199/1,179,988 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant has been observed in trans with a pathogenic variant in two siblings with primary ciliary dyskinesia in a single family (PMID: 11788826, 25186273). It has conflicting interpretations in ClinVar (ID: 287698). Computational evidence is uninformative for the missense substitution (REVEL = 0.510). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM3, PM2_Supporting, PP1. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 24, 2016	The p.R1454Q variant (also known as c.4361G>A), located in coding exon 28 of the DNAH5 gene, results from a G to A substitution at nucleotide position 4361. The arginine at codon 1454 is replaced by glutamine, an amino acid with highly similar properties. This variant was detected in two siblings with primary ciliary dyskensia (characterized by outer dynein arm defects on electron microscopy) who were compound heterozygous for another DNAH5 mutation; both siblings had immotile cilia and one sibling had situs inversus (Olbrich H, Nat. Genet. 2002 Feb; 30(2):143-4; Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Ex vivo cultures of these patients' epithelial airway showed absent cilia or membrane alterations in many cells and mislocalization of DNAH5 to the basal body region in the remaining cells (Olbrich H, Pediatr. Res. 2006 Mar; 59(3):418-22). Based on the available evidence, p.R1454Q is classified as a pathogenic mutation. -

Primary ciliary dyskinesia 3 Pathogenic:1 Uncertain:1

Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Feb 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 11, 2016	The DNAH5 c.4361G>A (p.Arg1454Gln) variant is a missense variant that has has been reported in four studies, all of which describe the same family of German origin (Olbrich et al. 2002; Olbrich et al. 2006; Loges et al. 2008; Raidt et al. 2014). The p.Arg1454Gln variant was found in a compound heterozygous state with a frameshift variant in two siblings with primary ciliary dyskinesia. The p.Arg1454Gln variant was absent from 200 control chromosomes (Olbrich et al. 2002) and is reported at a frequency of 0.00034 in the African population of the Exome Aggregation Consortium. Direct visualization of respiratory cells from the individuals carrying the variant showed an absence of cilia or membrane alterations. In the remaining ciliated cells, variant DNAH5 was absent from the ciliary axonemes and mislocalized to the basal body region (Olbrich et al. 2006; Loges et al. 2008). The evidence for this variant is limited. The p.Arg1454Gln variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 09, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.093	D
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.84		Loss of MoRF binding (P = 0.0211);
MVP		0.80
MPC		0.30
ClinPred		0.70	D
GERP RS		5.3
Varity_R		0.60
gMVP		0.53

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: rs542708170; hg19: chr5-13864741; COSMIC: COSV54215668;