5-13882732-A-G

Position:

• chr5-13882732-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001369.3(DNAH5):​c.3258T>C​(p.Leu1086Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 1,608,472 control chromosomes in the GnomAD database, including 50,011 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5340 hom., cov: 32)
  • Exomes 𝑓: 0.24 (44671 hom.)
• Consequence: DNAH5 NM_001369.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.268

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 5-13882732-A-G is Benign according to our data. Variant chr5-13882732-A-G is described in ClinVar as [Benign]. Clinvar id is 163154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13882732-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.268 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.3258T>C	p.Leu1086Leu	synonymous_variant	21/79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.3258T>C	p.Leu1086Leu	synonymous_variant	21/79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.3213T>C	p.Leu1071Leu	synonymous_variant	21/79			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-13857A>G		intron_variant		4
ENSG00000251423	ENST00000637153.1	n.214-13857A>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39386 AN: 151976 Hom.: 5337 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.238

GnomAD3 exomes AF: 0.253 AC: 63507 AN: 250522 Hom.: 8490 AF XY: 0.250 AC XY: 33832 AN XY: 135428

Gnomad AFR exome AF: 0.315

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.283

Gnomad EAS exome AF: 0.127

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.241

Gnomad NFE exome AF: 0.241

Gnomad OTH exome AF: 0.248

GnomAD4 exome AF: 0.244 AC: 355671 AN: 1456376 Hom.: 44671 Cov.: 31 AF XY: 0.244 AC XY: 177177 AN XY: 724798

Gnomad4 AFR exome AF: 0.310

Gnomad4 AMR exome AF: 0.331

Gnomad4 ASJ exome AF: 0.285

Gnomad4 EAS exome AF: 0.0974

Gnomad4 SAS exome AF: 0.251

Gnomad4 FIN exome AF: 0.236

Gnomad4 NFE exome AF: 0.243

Gnomad4 OTH exome AF: 0.246

GnomAD4 genome AF: 0.259 AC: 39404 AN: 152096 Hom.: 5340 Cov.: 32 AF XY: 0.259 AC XY: 19271 AN XY: 74356

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.286

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.233

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.235

Alfa AF: 0.241 Hom.: 5814

Bravo AF: 0.266

Asia WGS AF: 0.200 AC: 697 AN: 3478

EpiCase AF: 0.243

EpiControl AF: 0.249

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Leu1086Leu in exon 21 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 31.7% (1398/4406) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs10057007). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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: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 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	7.8
DANN	Benign	0.86

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: rs10057007; hg19: chr5-13882841;