rs4701997

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369.3(DNAH5):c.2296A>T(p.Ile766Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,613,488 control chromosomes in the GnomAD database, including 211,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.50 ( 19427 hom., cov: 32)

Exomes 𝑓: 0.51 ( 191617 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.01

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:

DNAH5 (HGNC:):

DNAH5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.2438915E-5).

BP6

Variant 5-13894785-T-A is Benign according to our data. Variant chr5-13894785-T-A is described in ClinVar as [Benign]. Clinvar id is 178753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13894785-T-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.2296A>T	p.Ile766Leu	missense_variant	16/79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.2296A>T	p.Ile766Leu	missense_variant	16/79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 linkuse as main transcript	c.2251A>T	p.Ile751Leu	missense_variant	16/79			ENSP00000505288.1	A0A7P0Z455
ENSG00000251423	ENST00000503244.2 linkuse as main transcript	n.254-1804T>A		intron_variant		4
ENSG00000251423	ENST00000637153.1 linkuse as main transcript	n.214-1804T>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.504

AC:

76485

AN:

151852

Hom.:

19411

Cov.:

show subpopulations

Gnomad AFR

AF:

0.530

Gnomad AMI

AF:

0.524

Gnomad AMR

AF:

0.500

Gnomad ASJ

AF:

0.527

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.610

Gnomad FIN

AF:

0.449

Gnomad MID

AF:

0.573

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.506

GnomAD3 exomes

AF:

0.500

AC:

125490

AN:

251066

Hom.:

32362

AF XY:

0.508

AC XY:

68880

AN XY:

135692

show subpopulations

Gnomad AFR exome

AF:

0.534

Gnomad AMR exome

AF:

0.497

Gnomad ASJ exome

AF:

0.526

Gnomad EAS exome

AF:

0.238

Gnomad SAS exome

AF:

0.628

Gnomad FIN exome

AF:

0.459

Gnomad NFE exome

AF:

0.509

Gnomad OTH exome

AF:

0.495

GnomAD4 exome

AF:

0.509

AC:

743312

AN:

1461518

Hom.:

191617

Cov.:

AF XY:

0.512

AC XY:

372466

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.538

Gnomad4 AMR exome

AF:

0.497

Gnomad4 ASJ exome

AF:

0.523

Gnomad4 EAS exome

AF:

0.242

Gnomad4 SAS exome

AF:

0.625

Gnomad4 FIN exome

AF:

0.457

Gnomad4 NFE exome

AF:

0.511

Gnomad4 OTH exome

AF:

0.501

GnomAD4 genome

AF:

0.504

AC:

76550

AN:

151970

Hom.:

19427

Cov.:

AF XY:

0.502

AC XY:

37314

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.530

Gnomad4 AMR

AF:

0.500

Gnomad4 ASJ

AF:

0.527

Gnomad4 EAS

AF:

0.243

Gnomad4 SAS

AF:

0.609

Gnomad4 FIN

AF:

0.449

Gnomad4 NFE

AF:

0.508

Gnomad4 OTH

AF:

0.508

Alfa

AF:

0.507

Hom.:

14802

Bravo

AF:

0.505

TwinsUK

AF:

0.509

AC:

1887

ALSPAC

AF:

0.528

AC:

2035

ESP6500AA

AF:

0.533

AC:

2349

ESP6500EA

AF:

0.508

AC:

4368

ExAC

AF:

0.507

AC:

61573

Asia WGS

AF:

0.453

AC:

1577

AN:

3478

EpiCase

AF:

0.510

EpiControl

AF:

0.512

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile766Leu in exon 16 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 49.2% (4232/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs4701997). -
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	Ambry Genetics	Nov 26, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Primary ciliary dyskinesia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
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 12, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.096

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.16

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.51

MetaRNN

Benign

0.000022

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

REVEL

Benign

0.088

Sift

Benign

0.31

Polyphen

0.0010

Vest4

0.088

MutPred

0.44

Gain of ubiquitination at K765 (P = 0.1047);

MPC

0.093

ClinPred

0.027

GERP RS

4.4

Varity_R

0.18

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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