rs4429853

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369.3(DNAH5):c.5115-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.363 in 1,611,676 control chromosomes in the GnomAD database, including 108,496 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12597 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95899 hom. )

Consequence

DNAH5
NM_001369.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00003832

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.128

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 5-13844998-A-G is Benign according to our data. Variant chr5-13844998-A-G is described in ClinVar as [Benign]. Clinvar id is 163149.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13844998-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.5115-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.5115-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.5070-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				A1

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60853

AN:

151824

Hom.:

12578

Cov.:

show subpopulations

Gnomad AFR

AF:

0.498

Gnomad AMI

AF:

0.416

Gnomad AMR

AF:

0.371

Gnomad ASJ

AF:

0.347

Gnomad EAS

AF:

0.607

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.315

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.353

Gnomad OTH

AF:

0.398

GnomAD3 exomes

AF:

0.379

AC:

94931

AN:

250624

Hom.:

18785

AF XY:

0.372

AC XY:

50483

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.502

Gnomad AMR exome

AF:

0.363

Gnomad ASJ exome

AF:

0.341

Gnomad EAS exome

AF:

0.630

Gnomad SAS exome

AF:

0.340

Gnomad FIN exome

AF:

0.320

Gnomad NFE exome

AF:

0.351

Gnomad OTH exome

AF:

0.369

GnomAD4 exome

AF:

0.359

AC:

524248

AN:

1459734

Hom.:

95899

Cov.:

AF XY:

0.358

AC XY:

259714

AN XY:

726308

show subpopulations

Gnomad4 AFR exome

AF:

0.497

Gnomad4 AMR exome

AF:

0.369

Gnomad4 ASJ exome

AF:

0.339

Gnomad4 EAS exome

AF:

0.559

Gnomad4 SAS exome

AF:

0.339

Gnomad4 FIN exome

AF:

0.326

Gnomad4 NFE exome

AF:

0.351

Gnomad4 OTH exome

AF:

0.370

GnomAD4 genome

AF:

0.401

AC:

60913

AN:

151942

Hom.:

12597

Cov.:

AF XY:

0.398

AC XY:

29538

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.499

Gnomad4 AMR

AF:

0.371

Gnomad4 ASJ

AF:

0.347

Gnomad4 EAS

AF:

0.607

Gnomad4 SAS

AF:

0.346

Gnomad4 FIN

AF:

0.315

Gnomad4 NFE

AF:

0.353

Gnomad4 OTH

AF:

0.396

Alfa

AF:

0.364

Hom.:

5062

Bravo

AF:

0.413

Asia WGS

AF:

0.454

AC:

1576

AN:

3478

EpiCase

AF:

0.349

EpiControl

AF:

0.345

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	5115-5T>C in intron 31 of DNAH5: This variant is not expected to have clinical s ignificance because it has been identified in 49.9% (2200/4406) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs4429853). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Primary ciliary dyskinesia

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 10, 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. -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.4

DANN

Benign

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000038

dbscSNV1_RF

Benign

0.0020

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over