rs761622153

chr5-13841112-G-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PVS1 PM2 PP5 BS1_Supporting

The NM_001369.3(DNAH5):c.5503C>T(p.Gln1835Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000294 in 1,461,602 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). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:2
• Conservation: PhyloP100: 9.97

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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-13841112-G-A is Pathogenic according to our data. Variant chr5-13841112-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 372356.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=1, Likely_pathogenic=2}. Variant chr5-13841112-G-A is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000294 (43/1461602) while in subpopulation MID AF= 0.00556 (32/5758). AF 95% confidence interval is 0.00405. There are 0 homozygotes in gnomad4_exome. There are 22 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.5503C>T	p.Gln1835Ter	stop_gained	34/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.5503C>T	p.Gln1835Ter	stop_gained	34/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.5458C>T	p.Gln1820Ter	stop_gained	34/79			A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250466 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135506

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000294 AC: 43 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22 AN XY: 727102

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome Cov.: 33

Alfa AF: 0.000102 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 11, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 11, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 25, 2020	- -
Pathogenic, criteria provided, single submitter	research	Human Genetics Section, Sidra Medicine	Feb 28, 2024	Loss of function is a known mechanism of disease in DNAH5 related primary ciliary dyskinesia (MIM#608644). Extremely low frequency in gnomAD population databases (Total allele frequency 0.000007985). ClinVar contains an entry for this variant (Variation ID: 372356). The variant is heterozygous in 4 siblings with primary ciliary dyskinesia. We thus classify the variant as pathogenic -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2016

The Q1835X variant in the DNAH5 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1835X variant 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. Therefore, we interpret Q1835X as a likely pathogenic variant. -

Primary ciliary dyskinesia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 13, 2022

This sequence change creates a premature translational stop signal (p.Gln1835*) 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 (rs761622153, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with a copy number gain of DNAH5 exon 1-50. In all individuals where phase was determined, the p.Gln1835* variant and the exon 1-50 copy number gain were on the same chromosome. As a result, it is unknown which copy of the DNAH5 gene this variant is located in, or how this variant impacts gene function. (Invitae). ClinVar contains an entry for this variant (Variation ID: 372356). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	48
Dann	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.8

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: rs761622153; hg19: chr5-13841221; COSMIC: COSV54254052;