rs2401809

Positions:

chr5-13754285-C-T

Variant summary

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

The NM_001369.3(DNAH5):c.10473G>A(p.Thr3491=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,613,622 control chromosomes in the GnomAD database, including 104,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9572 hom., cov: 32)

Exomes 𝑓: 0.36 ( 95037 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.38

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=-0.68).

BP6

Variant 5-13754285-C-T is Benign according to our data. Variant chr5-13754285-C-T is described in ClinVar as [Benign]. Clinvar id is 163136.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13754285-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.38 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.445 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.10473G>A	p.Thr3491=	synonymous_variant	62/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.10473G>A	p.Thr3491=	synonymous_variant	62/79	1	NM_001369.3	ENSP00000265104	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.10428G>A	p.Thr3476=	synonymous_variant	62/79			ENSP00000505288	A1

Frequencies

GnomAD3 genomes

AF:

0.349

AC:

53051

AN:

151864

Hom.:

9571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.340

Gnomad AMI

AF:

0.427

Gnomad AMR

AF:

0.320

Gnomad ASJ

AF:

0.335

Gnomad EAS

AF:

0.132

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.399

Gnomad MID

AF:

0.360

Gnomad NFE

AF:

0.362

Gnomad OTH

AF:

0.354

GnomAD3 exomes

AF:

0.347

AC:

87171

AN:

251064

Hom.:

16007

AF XY:

0.356

AC XY:

48244

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.338

Gnomad AMR exome

AF:

0.310

Gnomad ASJ exome

AF:

0.342

Gnomad EAS exome

AF:

0.112

Gnomad SAS exome

AF:

0.462

Gnomad FIN exome

AF:

0.386

Gnomad NFE exome

AF:

0.360

Gnomad OTH exome

AF:

0.340

GnomAD4 exome

AF:

0.357

AC:

522055

AN:

1461638

Hom.:

95037

Cov.:

AF XY:

0.361

AC XY:

262358

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.337

Gnomad4 AMR exome

AF:

0.310

Gnomad4 ASJ exome

AF:

0.338

Gnomad4 EAS exome

AF:

0.134

Gnomad4 SAS exome

AF:

0.453

Gnomad4 FIN exome

AF:

0.379

Gnomad4 NFE exome

AF:

0.360

Gnomad4 OTH exome

AF:

0.355

GnomAD4 genome

AF:

0.349

AC:

53074

AN:

151984

Hom.:

9572

Cov.:

AF XY:

0.352

AC XY:

26140

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.339

Gnomad4 AMR

AF:

0.320

Gnomad4 ASJ

AF:

0.335

Gnomad4 EAS

AF:

0.133

Gnomad4 SAS

AF:

0.461

Gnomad4 FIN

AF:

0.399

Gnomad4 NFE

AF:

0.362

Gnomad4 OTH

AF:

0.356

Alfa

AF:

0.339

Hom.:

5102

Bravo

AF:

0.337

Asia WGS

AF:

0.345

AC:

1197

AN:

3478

EpiCase

AF:

0.361

EpiControl

AF:

0.359

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	- -

Primary ciliary dyskinesia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 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 specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr3491Thr in exon 62 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 36.4% (3128/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2401809). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.066

DANN

Benign

0.48

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