5-13811666-T-C

Position:

chr5-13811666-T-C

Variant summary

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

The ENST00000265104.5(DNAH5):c.7388A>G(p.Gln2463Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,613,578 control chromosomes in the GnomAD database, including 38,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q2463P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.21 ( 3556 hom., cov: 32)

Exomes 𝑓: 0.21 ( 34597 hom. )

Consequence

DNAH5
ENST00000265104.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 7.95

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=0.0016318262).

BP6

Variant 5-13811666-T-C is Benign according to our data. Variant chr5-13811666-T-C is described in ClinVar as [Benign]. Clinvar id is 163142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13811666-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.522 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.7388A>G	p.Gln2463Arg	missense_variant	44/79	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.7388A>G	p.Gln2463Arg	missense_variant	44/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.7343A>G	p.Gln2448Arg	missense_variant	44/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.209

AC:

31767

AN:

152008

Hom.:

3559

Cov.:

show subpopulations

Gnomad AFR

AF:

0.195

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.170

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.539

Gnomad SAS

AF:

0.178

Gnomad FIN

AF:

0.192

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.207

Gnomad OTH

AF:

0.212

GnomAD3 exomes

AF:

0.214

AC:

53917

AN:

251392

Hom.:

6970

AF XY:

0.211

AC XY:

28665

AN XY:

135876

show subpopulations

Gnomad AFR exome

AF:

0.203

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.145

Gnomad EAS exome

AF:

0.553

Gnomad SAS exome

AF:

0.155

Gnomad FIN exome

AF:

0.193

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.199

GnomAD4 exome

AF:

0.210

AC:

306496

AN:

1461452

Hom.:

34597

Cov.:

AF XY:

0.208

AC XY:

151163

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.195

Gnomad4 AMR exome

AF:

0.162

Gnomad4 ASJ exome

AF:

0.148

Gnomad4 EAS exome

AF:

0.499

Gnomad4 SAS exome

AF:

0.158

Gnomad4 FIN exome

AF:

0.196

Gnomad4 NFE exome

AF:

0.208

Gnomad4 OTH exome

AF:

0.208

GnomAD4 genome

AF:

0.209

AC:

31780

AN:

152126

Hom.:

3556

Cov.:

AF XY:

0.206

AC XY:

15345

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.195

Gnomad4 AMR

AF:

0.170

Gnomad4 ASJ

AF:

0.152

Gnomad4 EAS

AF:

0.538

Gnomad4 SAS

AF:

0.178

Gnomad4 FIN

AF:

0.192

Gnomad4 NFE

AF:

0.207

Gnomad4 OTH

AF:

0.211

Alfa

AF:

0.210

Hom.:

7599

Bravo

AF:

0.212

TwinsUK

AF:

0.219

AC:

813

ALSPAC

AF:

0.211

AC:

813

ESP6500AA

AF:

0.202

AC:

888

ESP6500EA

AF:

0.205

AC:

1761

ExAC

AF:

0.215

AC:

26091

Asia WGS

AF:

0.307

AC:

1065

AN:

3478

EpiCase

AF:

0.200

EpiControl

AF:

0.202

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Primary ciliary dyskinesia 3

Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Gln2463Arg in exon 44 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 20.5% (1761/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs10078391). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 27989800) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.0

MutationTaster

Benign

2.1e-7

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.2

REVEL

Benign

0.15

Sift

Uncertain

0.017

Polyphen

0.39

Vest4

0.29

MPC

0.10

ClinPred

0.042

GERP RS

5.8

Varity_R

0.35

gMVP

0.62

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