rs6554827

Positions:

chr5-13864619-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_001369.3(DNAH5):c.4374G>T(p.Arg1458=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,476 control chromosomes in the GnomAD database, including 151,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12231 hom., cov: 32)

Exomes 𝑓: 0.43 ( 139070 hom. )

Consequence

DNAH5
NM_001369.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.676

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.3).

BP6

Variant 5-13864619-C-A is Benign according to our data. Variant chr5-13864619-C-A is described in ClinVar as [Benign]. Clinvar id is 178750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13864619-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.676 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.449 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.4374G>T	p.Arg1458=	synonymous_variant	28/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
DNAH5	ENST00000265104.5 linkuse as main transcript	c.4374G>T	p.Arg1458=	synonymous_variant	28/79	1	NM_001369.3	P4
	ENST00000503244.2 linkuse as main transcript	n.253+4064C>A		intron_variant, non_coding_transcript_variant		4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.4329G>T	p.Arg1443=	synonymous_variant	28/79			A1
	ENST00000637153.1 linkuse as main transcript	n.213+4104C>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.395

AC:

60025

AN:

151834

Hom.:

12213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.317

Gnomad AMI

AF:

0.323

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.356

Gnomad EAS

AF:

0.259

Gnomad SAS

AF:

0.463

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.332

Gnomad NFE

AF:

0.450

Gnomad OTH

AF:

0.401

GnomAD3 exomes

AF:

0.402

AC:

100972

AN:

251218

Hom.:

21353

AF XY:

0.410

AC XY:

55694

AN XY:

135752

show subpopulations

Gnomad AFR exome

AF:

0.307

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.359

Gnomad EAS exome

AF:

0.238

Gnomad SAS exome

AF:

0.475

Gnomad FIN exome

AF:

0.479

Gnomad NFE exome

AF:

0.445

Gnomad OTH exome

AF:

0.399

GnomAD4 exome

AF:

0.433

AC:

632584

AN:

1461524

Hom.:

139070

Cov.:

AF XY:

0.434

AC XY:

315392

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.320

Gnomad4 AMR exome

AF:

0.301

Gnomad4 ASJ exome

AF:

0.359

Gnomad4 EAS exome

AF:

0.258

Gnomad4 SAS exome

AF:

0.468

Gnomad4 FIN exome

AF:

0.478

Gnomad4 NFE exome

AF:

0.446

Gnomad4 OTH exome

AF:

0.416

GnomAD4 genome

AF:

0.395

AC:

60087

AN:

151952

Hom.:

12231

Cov.:

AF XY:

0.394

AC XY:

29272

AN XY:

74252

show subpopulations

Gnomad4 AFR

AF:

0.317

Gnomad4 AMR

AF:

0.342

Gnomad4 ASJ

AF:

0.356

Gnomad4 EAS

AF:

0.260

Gnomad4 SAS

AF:

0.465

Gnomad4 FIN

AF:

0.486

Gnomad4 NFE

AF:

0.449

Gnomad4 OTH

AF:

0.404

Alfa

AF:

0.426

Hom.:

17878

Bravo

AF:

0.375

Asia WGS

AF:

0.381

AC:

1327

AN:

3476

EpiCase

AF:

0.431

EpiControl

AF:

0.430

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	- -

Primary ciliary dyskinesia 3

Benign:3

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. -
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	- -

not specified

Benign:2

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	Arg1458Arg in exon 28 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 44.3% (3807/8600) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6554827). -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
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

-0.30

CADD

Benign

5.1

DANN

Benign

0.79

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