rs121908853

Positions:

• chr5-13901476-G-A
• chr5-13901476-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001369.3(DNAH5):​c.1828C>T​(p.Gln610Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000958 in 1,461,604 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.60

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 12 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 5-13901476-G-A is Pathogenic according to our data. Variant chr5-13901476-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 6480.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.1828C>T	p.Gln610Ter	stop_gained	14/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.1828C>T	p.Gln610Ter	stop_gained	14/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1	c.1783C>T	p.Gln595Ter	stop_gained	14/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247648 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134158

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461604 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727070

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 03, 2023

This sequence change creates a premature translational stop signal (p.Gln610*) 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 (rs121908853, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 11788826). ClinVar contains an entry for this variant (Variation ID: 6480). For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	A
Vest4		0.81
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs121908853; hg19: chr5-13901585;