rs3734111

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369.3(DNAH5):c.13359A>G(p.Thr4453=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,605,764 control chromosomes in the GnomAD database, including 226,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18362 hom., cov: 30)

Exomes 𝑓: 0.53 ( 207948 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -5.33

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 5-13701416-T-C is Benign according to our data. Variant chr5-13701416-T-C is described in ClinVar as [Benign]. Clinvar id is 178740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13701416-T-C is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.33 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.13359A>G	p.Thr4453=	synonymous_variant	77/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.13359A>G	p.Thr4453=	synonymous_variant	77/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.13314A>G	p.Thr4438=	synonymous_variant	77/79			A1
DNAH5	ENST00000683611.1 linkuse as main transcript	n.692A>G		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes

AF:

0.485

AC:

73509

AN:

151508

Hom.:

18346

Cov.:

show subpopulations

Gnomad AFR

AF:

0.375

Gnomad AMI

AF:

0.588

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.536

Gnomad EAS

AF:

0.433

Gnomad SAS

AF:

0.446

Gnomad FIN

AF:

0.530

Gnomad MID

AF:

0.500

Gnomad NFE

AF:

0.544

Gnomad OTH

AF:

0.499

GnomAD3 exomes

AF:

0.503

AC:

126419

AN:

251126

Hom.:

32362

AF XY:

0.503

AC XY:

68285

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.371

Gnomad AMR exome

AF:

0.493

Gnomad ASJ exome

AF:

0.529

Gnomad EAS exome

AF:

0.420

Gnomad SAS exome

AF:

0.444

Gnomad FIN exome

AF:

0.529

Gnomad NFE exome

AF:

0.547

Gnomad OTH exome

AF:

0.518

GnomAD4 exome

AF:

0.531

AC:

772654

AN:

1454136

Hom.:

207948

Cov.:

AF XY:

0.529

AC XY:

382630

AN XY:

723818

show subpopulations

Gnomad4 AFR exome

AF:

0.360

Gnomad4 AMR exome

AF:

0.493

Gnomad4 ASJ exome

AF:

0.526

Gnomad4 EAS exome

AF:

0.388

Gnomad4 SAS exome

AF:

0.443

Gnomad4 FIN exome

AF:

0.528

Gnomad4 NFE exome

AF:

0.551

Gnomad4 OTH exome

AF:

0.516

GnomAD4 genome

AF:

0.485

AC:

73568

AN:

151628

Hom.:

18362

Cov.:

AF XY:

0.482

AC XY:

35701

AN XY:

74066

show subpopulations

Gnomad4 AFR

AF:

0.375

Gnomad4 AMR

AF:

0.499

Gnomad4 ASJ

AF:

0.536

Gnomad4 EAS

AF:

0.433

Gnomad4 SAS

AF:

0.446

Gnomad4 FIN

AF:

0.530

Gnomad4 NFE

AF:

0.544

Gnomad4 OTH

AF:

0.501

Alfa

AF:

0.537

Hom.:

41335

Bravo

AF:

0.479

Asia WGS

AF:

0.455

AC:

1584

AN:

3478

EpiCase

AF:

0.540

EpiControl

AF:

0.552

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr4453Thr in exon 77 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 45.3% (3894/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs3734111). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Primary ciliary dyskinesia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

Cadd

Benign

0.0020

Dann

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over