rs767716511

Variant names:

• chr5-13701349-G-A
• rs767716511
• NM_001369.3:c.13426C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001369.3(DNAH5):​c.13426C>T​(p.Arg4476*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,850 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: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: DNAH5 NM_001369.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.96
• Publications: 1 publications found

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]

DNAH5 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 5-13701349-G-A is Pathogenic according to our data. Variant chr5-13701349-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 454743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.13426C>T	p.Arg4476*	stop_gained	Exon 77 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.13426C>T	p.Arg4476*	stop_gained	Exon 77 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.13381C>T	p.Arg4461*	stop_gained	Exon 77 of 79			ENSP00000505288.1
DNAH5	ENST00000683611.1	n.759C>T		non_coding_transcript_exon_variant	Exon 3 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251386 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461850 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727230

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111978

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:2

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg4476*) 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 (rs767716511, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with primary ciliary dyskinesia (PMID: 16627867; internal data). ClinVar contains an entry for this variant (Variation ID: 454743). For these reasons, this variant has been classified as Pathogenic. -

Jul 21, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Aug 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.0
Vest4		0.79
GERP RS		3.6
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs767716511; hg19: chr5-13701458; COSMIC: COSV108794782;