rs1530498

Variant names:

• chr5-13902111-T-C
• rs1530498
• NM_001369.3:c.1672A>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.1672A>G​(p.Thr558Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 1,603,616 control chromosomes in the GnomAD database, including 131,552 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T558T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.35 (10499 hom., cov: 33)
  • Exomes 𝑓: 0.40 (121053 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.21
• Publications: 34 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=2.1918752E-6).
• BP6: Variant 5-13902111-T-C is Benign according to our data. Variant chr5-13902111-T-C is described in ClinVar as Benign. ClinVar VariationId is 163157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.1672A>G	p.Thr558Ala	missense_variant	Exon 13 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.1672A>G	p.Thr558Ala	missense_variant	Exon 13 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.1627A>G	p.Thr543Ala	missense_variant	Exon 13 of 79			ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.353 AC: 53630 AN: 152060 Hom.: 10497 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.387

Gnomad ASJ AF: 0.422

Gnomad EAS AF: 0.761

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.399 AC: 97352 AN: 244236 AF XY: 0.396

Gnomad AFR exome AF: 0.183

Gnomad AMR exome AF: 0.383

Gnomad ASJ exome AF: 0.429

Gnomad EAS exome AF: 0.761

Gnomad FIN exome AF: 0.370

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.400 AC: 580750 AN: 1451438 Hom.: 121053 Cov.: 32 AF XY: 0.398 AC XY: 287102 AN XY: 721874

African (AFR) AF: 0.177 AC: 5918 AN: 33366

American (AMR) AF: 0.384 AC: 17023 AN: 44324

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 11099 AN: 25898

East Asian (EAS) AF: 0.758 AC: 29979 AN: 39538

South Asian (SAS) AF: 0.305 AC: 26085 AN: 85626

European-Finnish (FIN) AF: 0.378 AC: 19882 AN: 52616

Middle Eastern (MID) AF: 0.421 AC: 2416 AN: 5740

European-Non Finnish (NFE) AF: 0.402 AC: 444148 AN: 1104326

Other (OTH) AF: 0.403 AC: 24200 AN: 60004

GnomAD4 genome AF: 0.352 AC: 53628 AN: 152178 Hom.: 10499 Cov.: 33 AF XY: 0.353 AC XY: 26254 AN XY: 74394

African (AFR) AF: 0.193 AC: 8020 AN: 41550

American (AMR) AF: 0.387 AC: 5919 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 1466 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3943 AN: 5176

South Asian (SAS) AF: 0.322 AC: 1555 AN: 4828

European-Finnish (FIN) AF: 0.366 AC: 3863 AN: 10568

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27693 AN: 67980

Other (OTH) AF: 0.360 AC: 759 AN: 2110

Alfa AF: 0.397 Hom.: 54253

Bravo AF: 0.350

TwinsUK AF: 0.406 AC: 1505

ALSPAC AF: 0.386 AC: 1489

ESP6500AA AF: 0.189 AC: 831

ESP6500EA AF: 0.406 AC: 3481

ExAC AF: 0.388 AC: 47069

Asia WGS AF: 0.479 AC: 1664 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Thr558Ala in exon 13 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 40.6% (3481/8584) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs1530498). -

-

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

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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 3 Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.072	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0000022	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.080
Sift	Benign	0.79	T
Polyphen		0.0020	B
Vest4		0.082
MPC		0.26
ClinPred		0.015	T
GERP RS		2.6
Varity_R		0.19
gMVP		0.46
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1530498; hg19: chr5-13902220; COSMIC: COSV107306137; COSMIC: COSV107306137;