rs6554827

Positions:

• chr5-13864619-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.676

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]

(HGNC:):

ACMG classification

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	c.4374G>T	p.Arg1458=	synonymous_variant	28/79	ENST00000265104.5

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.395 AC: 60025 AN: 151834 Hom.: 12213 Cov.: 32

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

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.: 46 AF XY: 0.434 AC XY: 315392 AN XY: 727084

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.: 32 AF XY: 0.394 AC XY: 29272 AN XY: 74252

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:9

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	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	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	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: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	-0.30
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

Other links and lift over

dbSNP: rs6554827; hg19: chr5-13864728; COSMIC: COSV54212419;