rs1530498

Positions:

• chr5-13902111-T-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 163157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13902111-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DNAH5	NM_001369.3	c.1672A>G	p.Thr558Ala	missense_variant	13/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.1672A>G	p.Thr558Ala	missense_variant	13/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.1627A>G	p.Thr543Ala	missense_variant	13/79			A1

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

GnomAD3 exomes AF: 0.399 AC: 97352 AN: 244236 Hom.: 21075 AF XY: 0.396 AC XY: 52293 AN XY: 131902

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 SAS exome AF: 0.303

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

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.384

Gnomad4 ASJ exome AF: 0.429

Gnomad4 EAS exome AF: 0.758

Gnomad4 SAS exome AF: 0.305

Gnomad4 FIN exome AF: 0.378

Gnomad4 NFE exome AF: 0.402

Gnomad4 OTH exome AF: 0.403

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

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.387

Gnomad4 ASJ AF: 0.422

Gnomad4 EAS AF: 0.762

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.407

Gnomad4 OTH AF: 0.360

Alfa AF: 0.405 Hom.: 30171

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

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	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). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 3 Benign:2

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

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
MutationTaster	Benign	0.00037	P
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

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

LitVar

Other links and lift over

dbSNP: rs1530498; hg19: chr5-13902220;