rs339445

Variant names:

Variant summary

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

The NM_001369.3(DNAH5):c.36T>G(p.His12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.938 in 1,613,616 control chromosomes in the GnomAD database, including 710,864 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 0.93 ( 65399 hom., cov: 31)

Exomes 𝑓: 0.94 ( 645465 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.762

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=5.602909E-7).

BP6

Variant 5-13944403-A-C is Benign according to our data. Variant chr5-13944403-A-C is described in ClinVar as [Benign]. Clinvar id is 178760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13944403-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.36T>G	p.His12Gln	missense_variant	Exon 1 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.36T>G	p.His12Gln	missense_variant	Exon 1 of 79	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 link	c.13-13159T>G		intron_variant	Intron 1 of 78			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.926

AC:

140894

AN:

152092

Hom.:

65356

Cov.:

show subpopulations

Gnomad AFR

AF:

0.886

Gnomad AMI

AF:

0.998

Gnomad AMR

AF:

0.936

Gnomad ASJ

AF:

0.957

Gnomad EAS

AF:

0.886

Gnomad SAS

AF:

0.919

Gnomad FIN

AF:

0.979

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.942

Gnomad OTH

AF:

0.924

GnomAD3 exomes

AF:

0.936

AC:

234735

AN:

250786

Hom.:

110008

AF XY:

0.935

AC XY:

126752

AN XY:

135564

show subpopulations

Gnomad AFR exome

AF:

0.884

Gnomad AMR exome

AF:

0.956

Gnomad ASJ exome

AF:

0.953

Gnomad EAS exome

AF:

0.881

Gnomad SAS exome

AF:

0.917

Gnomad FIN exome

AF:

0.977

Gnomad NFE exome

AF:

0.942

Gnomad OTH exome

AF:

0.930

GnomAD4 exome

AF:

0.940

AC:

1373106

AN:

1461406

Hom.:

645465

Cov.:

AF XY:

0.939

AC XY:

682495

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.881

Gnomad4 AMR exome

AF:

0.954

Gnomad4 ASJ exome

AF:

0.953

Gnomad4 EAS exome

AF:

0.900

Gnomad4 SAS exome

AF:

0.914

Gnomad4 FIN exome

AF:

0.978

Gnomad4 NFE exome

AF:

0.943

Gnomad4 OTH exome

AF:

0.928

GnomAD4 genome

AF:

0.926

AC:

140995

AN:

152210

Hom.:

65399

Cov.:

AF XY:

0.927

AC XY:

69016

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.885

Gnomad4 AMR

AF:

0.936

Gnomad4 ASJ

AF:

0.957

Gnomad4 EAS

AF:

0.886

Gnomad4 SAS

AF:

0.918

Gnomad4 FIN

AF:

0.979

Gnomad4 NFE

AF:

0.942

Gnomad4 OTH

AF:

0.925

Alfa

AF:

0.936

Hom.:

165288

Bravo

AF:

0.922

TwinsUK

AF:

0.947

AC:

3511

ALSPAC

AF:

0.948

AC:

3652

ESP6500AA

AF:

0.894

AC:

3937

ESP6500EA

AF:

0.942

AC:

8101

ExAC

AF:

0.936

AC:

113608

Asia WGS

AF:

0.907

AC:

3154

AN:

3478

EpiCase

AF:

0.934

EpiControl

AF:

0.935

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His12Gln in exon 1 of DNAH5: This variant is not expected to have clinical signi ficance because it has been identified in 10.6% (469/4406) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs339445). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 26, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.74

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.027

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.14

MetaRNN

Benign

5.6e-7

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.1

PrimateAI

Uncertain

0.53

PROVEAN

Benign

1.3

REVEL

Benign

0.091

Sift

Benign

1.0

Polyphen

0.0

Vest4

0.041

MutPred

0.077

Gain of helix (P = 0.0425);

MPC

0.094

ClinPred

0.0062

GERP RS

3.8

Varity_R

0.053

gMVP

0.14

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

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