5-13916424-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001369.3(DNAH5):c.1121T>C(p.Ile374Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,558,784 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. I374I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00059 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 4 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11B:1

Conservation

PhyloP100: 9.03

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21734911).

BS2

High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.1121T>C	p.Ile374Thr	missense	Exon 9 of 79	NP_001360.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.1121T>C	p.Ile374Thr	missense	Exon 9 of 79	ENSP00000265104.4
DNAH5	ENST00000681290.1		c.1076T>C	p.Ile359Thr	missense	Exon 9 of 79	ENSP00000505288.1
DNAH5	ENST00000508040.1	TSL:2	n.1529T>C		non_coding_transcript_exon	Exon 9 of 12

Frequencies

GnomAD3 genomes

AF:

0.000585

AC:

AN:

152012

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00113

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000751

AC:

188

AN:

250334

AF XY:

0.000820

show subpopulations

Gnomad AFR exome

AF:

0.000496

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00128

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.00131

AC:

1839

AN:

1406654

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

867

AN XY:

702782

show subpopulations

African (AFR)

AF:

0.000186

AC:

AN:

32244

American (AMR)

AF:

0.0000450

AC:

AN:

44412

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25518

East Asian (EAS)

AF:

0.00

AC:

AN:

38886

South Asian (SAS)

AF:

0.000705

AC:

AN:

85092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52650

Middle Eastern (MID)

AF:

0.000180

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

0.00163

AC:

1734

AN:

1063914

Other (OTH)

AF:

0.000617

AC:

AN:

58390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000585

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.000471

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41564

American (AMR)

AF:

0.000131

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000829

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00113

AC:

AN:

67938

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.000638

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000684

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 3

Pathogenic:1Uncertain:5

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 10, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Sep 22, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jul 31, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as VUS-3B. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 for a recessive condition (v4: 1918 heterozygote(s), 5 homozygote(s)) . Additional information: Variant is predicted to result in a missense amino acid change from Ile to Thr; This variant is heterozygous; This gene is associated with autosomal recessive disease; Alternative amino acid change(s) at the same position are present in gnomAD (highest allele count: v4: 5 heterozygote(s), 0 homozygote(s)); Previous evidence of pathogenicity for this variant is inconclusive. It has been classified a variant of uncertain significance and once as likely benign by clinical laboratories (ClinVar). In addition, it has been reported in a compound heterozygous child affected with primary ciliary dyskinesia with situs inversus (PMID: 23261302); No published functional evidence has been identified for this variant; No comparable missense variants have previous evidence for pathogenicity; Variant is located in the annotated N-terminal region 1 dynein heavy chain domain (DECIPHER); Missense variant with inconclusive in silico prediction and uninformative conservation; Loss of function is a known mechanism of disease in this gene and is associated with primary ciliary dyskinesia 3, with or without situs inversus (MIM#608644).

Jul 15, 2021

Genetics and Molecular Pathology, SA Pathology

Significance:Uncertain significance

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.

Primary ciliary dyskinesia

Uncertain:3Benign:1

Oct 29, 2019

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.I374T variant (also known as c.1121T>C), located in coding exon 9 of the DNAH5 gene, results from a T to C substitution at nucleotide position 1121. The isoleucine at codon 374 is replaced by threonine, an amino acid with similar properties. This variant was identified in a child with primary ciliary dyskinesia and situs inversus in conjunction with another DNAH5 variant in trans (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.071% (201/281530) total alleles studied. The highest observed frequency was 0.162% (82/50458) of Northwestern European alleles. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 18, 2019

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 10, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Uncertain:3

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

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Jun 29, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The I374T variant in the DNAH5 gene has been reported previously in trans with another DNAH5 variant in an individual with primary ciliary dyskinesia (Knowles et al., 2013). The I374T variant is observed in 63/65,796 (0.096%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The I374T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I374T as a variant of uncertain significance.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.18

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.22

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.8

PhyloP100

9.0

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

Polyphen

0.070

Vest4

0.83

MVP

0.68

MPC

0.12

ClinPred

0.097

GERP RS

5.3

Varity_R

0.54

gMVP

0.70

Mutation Taster

=43/57

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over