rs771663107

Positions:

• chr5-13865675-G-A

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.4348C>T​(p.Gln1450Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000707 in 1,554,958 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.99

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 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 5-13865675-G-A is Pathogenic according to our data. Variant chr5-13865675-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 208992.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.4348C>T	p.Gln1450Ter	stop_gained	27/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.4348C>T	p.Gln1450Ter	stop_gained	27/79	1	NM_001369.3	ENSP00000265104	P4
	ENST00000503244.2	n.253+5120G>A		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1	c.4303C>T	p.Gln1435Ter	stop_gained	27/79			ENSP00000505288	A1
	ENST00000637153.1	n.213+5160G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00110

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000713 AC: 10 AN: 1402828 Hom.: 0 Cov.: 27 AF XY: 0.00000713 AC XY: 5 AN XY: 701682

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: 0.00000850

Gnomad4 OTH exome AF: 0.0000171

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152130 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74298

Gnomad4 AFR AF: 0.00

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 08, 2014	The p.Q1450* pathogenic mutation (also known as c.4348C>T) located in coding exon 27 of the DNAH5 gene, results from a C to T substitution at nucleotide position 4348. This changes the amino acid from a glutamine to a stop codon within coding exon 27. Eight members of a consanguineous Amish family from Pennsylvania who all had neonatal respiratory distress, situs inversus totalis, chronic pneumonia, or rhinosinusitis were found to be homozygous for this mutation. This paper also identified four additional affected individuals who were either homozygous or heterozygous (phase was confirmed trans through parental testing) for this mutation (Ferkol TW, et al. J. Pediatr. 2013 Aug; 163(2):383-7). Another study identified two affected individuals who each carried another mutation, Q3455H and E4133*, in conjunction with this mutation; however, phase was not specified (Failly M, et al. J. Med. Genet. 2009 Apr; 46(4):281-6). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 19, 2021	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change creates a premature translational stop signal (p.Gln1450*) 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 present in population databases (rs771663107, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 19357118, 23477994). ClinVar contains an entry for this variant (Variation ID: 208992). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 3 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 27, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The stop gained p.Q1450* in DNAH5 (NM_001369.3) has been previously reported in homozygous state in affected individuals including those of Amish origin (Ferkol TW et al; Strauss KA et al). The variant has been submitted to ClinVar as Pathogenic. Although the variant is present at 0.0004% in gnomAD Exomes, it has the flag "Failed Random Forest" and may not represent the true population frequency. The p.Q1450* variant is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Kartagener syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs771663107; hg19: chr5-13865784;