rs10513155

Positions:

Variant summary

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

The ENST00000265104.5(DNAH5):c.8586G>T(p.Leu2862Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,654 control chromosomes in the GnomAD database, including 58,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L2862L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.24 ( 4494 hom., cov: 32)

Exomes 𝑓: 0.27 ( 54244 hom. )

Consequence

DNAH5
ENST00000265104.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.376

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048581064).

BP6

Variant 5-13788777-C-A is Benign according to our data. Variant chr5-13788777-C-A is described in ClinVar as [Benign]. Clinvar id is 178745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13788777-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.272 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.8586G>T	p.Leu2862Phe	missense_variant	51/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.8586G>T	p.Leu2862Phe	missense_variant	51/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.8541G>T	p.Leu2847Phe	missense_variant	51/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.237

AC:

36061

AN:

151964

Hom.:

4494

Cov.:

show subpopulations

Gnomad AFR

AF:

0.166

Gnomad AMI

AF:

0.371

Gnomad AMR

AF:

0.263

Gnomad ASJ

AF:

0.328

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.217

Gnomad FIN

AF:

0.207

Gnomad MID

AF:

0.354

Gnomad NFE

AF:

0.275

Gnomad OTH

AF:

0.259

GnomAD3 exomes

AF:

0.254

AC:

63945

AN:

251304

Hom.:

8430

AF XY:

0.258

AC XY:

35012

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.160

Gnomad AMR exome

AF:

0.253

Gnomad ASJ exome

AF:

0.334

Gnomad EAS exome

AF:

0.220

Gnomad SAS exome

AF:

0.226

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.280

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.269

AC:

393289

AN:

1461572

Hom.:

54244

Cov.:

AF XY:

0.268

AC XY:

194868

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.169

Gnomad4 AMR exome

AF:

0.255

Gnomad4 ASJ exome

AF:

0.334

Gnomad4 EAS exome

AF:

0.181

Gnomad4 SAS exome

AF:

0.225

Gnomad4 FIN exome

AF:

0.221

Gnomad4 NFE exome

AF:

0.279

Gnomad4 OTH exome

AF:

0.277

GnomAD4 genome

AF:

0.237

AC:

36063

AN:

152082

Hom.:

4494

Cov.:

AF XY:

0.236

AC XY:

17539

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.166

Gnomad4 AMR

AF:

0.263

Gnomad4 ASJ

AF:

0.328

Gnomad4 EAS

AF:

0.212

Gnomad4 SAS

AF:

0.214

Gnomad4 FIN

AF:

0.207

Gnomad4 NFE

AF:

0.275

Gnomad4 OTH

AF:

0.256

Alfa

AF:

0.278

Hom.:

15499

Bravo

AF:

0.239

TwinsUK

AF:

0.275

AC:

1018

ALSPAC

AF:

0.277

AC:

1068

ESP6500AA

AF:

0.163

AC:

719

ESP6500EA

AF:

0.289

AC:

2482

ExAC

AF:

0.252

AC:

30634

Asia WGS

AF:

0.212

AC:

738

AN:

3478

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	Leu2862Phe in exon 51 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 28.9% (2482/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs10513155). -
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	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. -
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	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

8.4

DANN

Benign

0.94

DEOGEN2

Benign

0.15

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.54

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.5

MutationTaster

Benign

0.96

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.8

REVEL

Benign

0.097

Sift

Benign

0.69

Polyphen

0.0

Vest4

0.018

MutPred

0.14

Gain of methylation at K2860 (P = 0.0635);

MPC

0.31

ClinPred

0.0049

GERP RS

4.0

Varity_R

0.057

gMVP

0.43

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