rs339445

Variant names:

• chr5-13944403-A-C
• rs339445
• NM_001369.3:c.36T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 14/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.762
• Publications: 31 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 178760.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.936 is higher than 0.05.

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.36T>G	p.His12Gln	missense	Exon 1 of 79	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.36T>G	p.His12Gln	missense	Exon 1 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.13-13159T>G		intron	N/A	ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.926 AC: 140894 AN: 152092 Hom.: 65356 Cov.: 31

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

GnomAD2 exomes AF: 0.936 AC: 234735 AN: 250786 AF XY: 0.935

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 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.: 50 AF XY: 0.939 AC XY: 682495 AN XY: 727044

African (AFR) AF: 0.881 AC: 29499 AN: 33468

American (AMR) AF: 0.954 AC: 42637 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.953 AC: 24912 AN: 26132

East Asian (EAS) AF: 0.900 AC: 35718 AN: 39688

South Asian (SAS) AF: 0.914 AC: 78869 AN: 86254

European-Finnish (FIN) AF: 0.978 AC: 51998 AN: 53180

Middle Eastern (MID) AF: 0.862 AC: 4968 AN: 5766

European-Non Finnish (NFE) AF: 0.943 AC: 1048494 AN: 1111820

Other (OTH) AF: 0.928 AC: 56011 AN: 60384

GnomAD4 genome AF: 0.926 AC: 140995 AN: 152210 Hom.: 65399 Cov.: 31 AF XY: 0.927 AC XY: 69016 AN XY: 74420

African (AFR) AF: 0.885 AC: 36753 AN: 41512

American (AMR) AF: 0.936 AC: 14312 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.957 AC: 3321 AN: 3470

East Asian (EAS) AF: 0.886 AC: 4577 AN: 5168

South Asian (SAS) AF: 0.918 AC: 4424 AN: 4820

European-Finnish (FIN) AF: 0.979 AC: 10387 AN: 10610

Middle Eastern (MID) AF: 0.861 AC: 253 AN: 294

European-Non Finnish (NFE) AF: 0.942 AC: 64101 AN: 68024

Other (OTH) AF: 0.925 AC: 1957 AN: 2116

Alfa AF: 0.933 Hom.: 229160

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

Submissions by phenotype

not specified Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:3

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.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Primary ciliary dyskinesia 3 Benign:3

Jun 15, 2021

Pars Genome 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.

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	18
DANN	Benign	0.63
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	5.6e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.1	N
PhyloP100		0.76
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
MutPred		0.077		Gain of helix (P = 0.0425)
MPC		0.094
ClinPred		0.0062	T
GERP RS		3.8
PromoterAI		0.013	Neutral
Varity_R		0.053
gMVP		0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs339445; hg19: chr5-13944512; COSMIC: COSV54244960;