rs143567667

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001369.3(DNAH5):c.4510G>C(p.Gly1504Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,614,126 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G1504G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00035 ( 1 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 7.44

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 3
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

DNAH5 links:

ENSG00000251423 (HGNC:40187):

ENSG00000251423 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012972176).

BP6

Variant 5-13864483-C-G is Benign according to our data. Variant chr5-13864483-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227325.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00273 (415/152278) while in subpopulation AFR AF = 0.00936 (389/41562). AF 95% confidence interval is 0.00859. There are 4 homozygotes in GnomAd4. There are 208 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.4510G>C	p.Gly1504Arg	missense_variant	Exon 28 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DNAH5	ENST00000265104.5 link	c.4510G>C	p.Gly1504Arg	missense_variant	Exon 28 of 79	1	NM_001369.3	ENSP00000265104.4	Q8TE73
DNAH5	ENST00000681290.1 link	c.4465G>C	p.Gly1489Arg	missense_variant	Exon 28 of 79			ENSP00000505288.1	A0A7P0Z455
ENSG00000251423	ENST00000503244.2 link	n.253+3928C>G		intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1 link	n.213+3968C>G		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00936

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.000728

AC:

183

AN:

251360

AF XY:

0.000464

show subpopulations

Gnomad AFR exome

AF:

0.00855

Gnomad AMR exome

AF:

0.000810

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000346

AC:

506

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000308

AC XY:

224

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.0103

AC:

345

AN:

33478

American (AMR)

AF:

0.000783

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000459

AC:

AN:

1111992

Other (OTH)

AF:

0.000944

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

130

162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00273

AC:

415

AN:

152278

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

208

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00936

AC:

389

AN:

41562

American (AMR)

AF:

0.00111

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68012

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000209

Hom.:

Bravo

AF:

0.00310

ESP6500AA

AF:

0.00908

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000848

AC:

103

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:3

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 14, 2016

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. -

Nov 11, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Primary ciliary dyskinesia 3

Uncertain:1Benign:1

Feb 25, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 16, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Gly1504Arg in exon 28 of DNAH5: This variant is not expected to have clinical significance because it has been identified in 0.8% (86/10378) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs143567667). -

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

DNAH5: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.013

MetaSVM

Uncertain

-0.24

MutationAssessor

Pathogenic

3.1

PhyloP100

7.4

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.4

REVEL

Uncertain

0.35

Sift

Benign

0.13

Polyphen

0.74

Vest4

0.43

MutPred

0.57

Gain of MoRF binding (P = 0.0155);

MVP

0.85

MPC

0.54

ClinPred

0.069

GERP RS

5.3

Varity_R

0.52

gMVP

0.62

Mutation Taster

=47/53

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs143567667

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over