rs148891849

chr5-13841895-G-Achr5-13841895-G-Cchr5-13841895-G-T

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.5281C>T(p.Arg1761Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000065 in 984,892 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R1761R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000065 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.99

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]

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 5-13841895-G-A is Pathogenic according to our data. Variant chr5-13841895-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 220475.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.5281C>T	p.Arg1761Ter	stop_gained	33/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.5281C>T	p.Arg1761Ter	stop_gained	33/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.5236C>T	p.Arg1746Ter	stop_gained	33/79			A1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 108870 Hom.: 0 Cov.: 25 FAILED QC

Gnomad AFR AF: 0.0000357

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: 0.0000171

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000216 AC: 5 AN: 231214 Hom.: 0 AF XY: 0.0000159 AC XY: 2 AN XY: 125594

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000365

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 64 AN: 984892 Hom.: 0 Cov.: 26 AF XY: 0.0000616 AC XY: 31 AN XY: 502840

Gnomad4 AFR exome AF: 0.0000425

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.0000226

Gnomad4 NFE exome AF: 0.0000846

Gnomad4 OTH exome AF: 0.0000244

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000184 AC: 2 AN: 108870 Hom.: 0 Cov.: 25 AF XY: 0.0000203 AC XY: 1 AN XY: 49190

Gnomad4 AFR AF: 0.0000357

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: 0.0000171

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2023	This sequence change creates a premature translational stop signal (p.Arg1761*) 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 (rs148891849, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867, 19357118). ClinVar contains an entry for this variant (Variation ID: 220475). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Centre for Genomic and Experimental Medicine, University of Edinburgh	Apr 01, 2020	- -

Primary ciliary dyskinesia 3 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 05, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.65
Cadd	Pathogenic	46
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.95
GERP RS		5.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: -25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148891849; hg19: chr5-13842004; COSMIC: COSV54258035;