rs1348689

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001369.3(DNAH5):c.6264C>T(p.Ala2088=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,612,658 control chromosomes in the GnomAD database, including 114,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2088A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 12283 hom., cov: 33)

Exomes 𝑓: 0.37 ( 101984 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.832

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 5-13829690-G-A is Benign according to our data. Variant chr5-13829690-G-A is described in ClinVar as [Benign]. Clinvar id is 163145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13829690-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.832 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.592 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.6264C>T	p.Ala2088=	synonymous_variant	38/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.6264C>T	p.Ala2088=	synonymous_variant	38/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.6219C>T	p.Ala2073=	synonymous_variant	38/79			A1
DNAH5	ENST00000683090.1 linkuse as main transcript	n.1195C>T		non_coding_transcript_exon_variant	3/7

Frequencies

GnomAD3 genomes

AF:

0.398

AC:

60495

AN:

151858

Hom.:

12267

Cov.:

show subpopulations

Gnomad AFR

AF:

0.461

Gnomad AMI

AF:

0.456

Gnomad AMR

AF:

0.383

Gnomad ASJ

AF:

0.366

Gnomad EAS

AF:

0.610

Gnomad SAS

AF:

0.332

Gnomad FIN

AF:

0.317

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.366

Gnomad OTH

AF:

0.400

GnomAD3 exomes

AF:

0.385

AC:

96523

AN:

250998

Hom.:

19222

AF XY:

0.379

AC XY:

51433

AN XY:

135666

show subpopulations

Gnomad AFR exome

AF:

0.464

Gnomad AMR exome

AF:

0.373

Gnomad ASJ exome

AF:

0.362

Gnomad EAS exome

AF:

0.624

Gnomad SAS exome

AF:

0.330

Gnomad FIN exome

AF:

0.325

Gnomad NFE exome

AF:

0.366

Gnomad OTH exome

AF:

0.381

GnomAD4 exome

AF:

0.371

AC:

541740

AN:

1460680

Hom.:

101984

Cov.:

AF XY:

0.369

AC XY:

267886

AN XY:

726712

show subpopulations

Gnomad4 AFR exome

AF:

0.459

Gnomad4 AMR exome

AF:

0.378

Gnomad4 ASJ exome

AF:

0.359

Gnomad4 EAS exome

AF:

0.562

Gnomad4 SAS exome

AF:

0.330

Gnomad4 FIN exome

AF:

0.328

Gnomad4 NFE exome

AF:

0.366

Gnomad4 OTH exome

AF:

0.380

GnomAD4 genome

AF:

0.398

AC:

60548

AN:

151978

Hom.:

12283

Cov.:

AF XY:

0.396

AC XY:

29383

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.461

Gnomad4 AMR

AF:

0.383

Gnomad4 ASJ

AF:

0.366

Gnomad4 EAS

AF:

0.610

Gnomad4 SAS

AF:

0.331

Gnomad4 FIN

AF:

0.317

Gnomad4 NFE

AF:

0.366

Gnomad4 OTH

AF:

0.397

Alfa

AF:

0.362

Hom.:

6506

Bravo

AF:

0.411

Asia WGS

AF:

0.454

AC:

1578

AN:

3478

EpiCase

AF:

0.370

EpiControl

AF:

0.364

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala2088Ala in exon 38 of DNAH5: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 45.6% (2011/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1348689). -

Primary ciliary dyskinesia

Benign:3

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. -
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 10, 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

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.8

DANN

Benign

0.64

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

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