NM_001369.3:c.3258T>C

Variant names:

• chr5-13882732-A-G
• rs10057007
• NM_001369.3:c.3258T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251423 (HGNC:40187):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 163154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001369.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	NM_001369.3	MANE Select	c.3258T>C	p.Leu1086Leu	synonymous	Exon 21 of 79	NP_001360.1
	DNAH5-AS1	NR_199035.1		n.118-13857A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.3258T>C	p.Leu1086Leu	synonymous	Exon 21 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.3213T>C	p.Leu1071Leu	synonymous	Exon 21 of 79	ENSP00000505288.1
	ENSG00000251423	ENST00000503244.2	TSL:4	n.254-13857A>G		intron	N/A

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

GnomAD2 exomes AF: 0.253 AC: 63507 AN: 250522 AF XY: 0.250

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 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

African (AFR) AF: 0.310 AC: 10341 AN: 33380

American (AMR) AF: 0.331 AC: 14779 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.285 AC: 7440 AN: 26086

East Asian (EAS) AF: 0.0974 AC: 3862 AN: 39664

South Asian (SAS) AF: 0.251 AC: 21629 AN: 86096

European-Finnish (FIN) AF: 0.236 AC: 12586 AN: 53266

Middle Eastern (MID) AF: 0.288 AC: 1656 AN: 5756

European-Non Finnish (NFE) AF: 0.243 AC: 268582 AN: 1107226

Other (OTH) AF: 0.246 AC: 14796 AN: 60210

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

African (AFR) AF: 0.307 AC: 12752 AN: 41506

American (AMR) AF: 0.280 AC: 4276 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 990 AN: 3462

East Asian (EAS) AF: 0.117 AC: 610 AN: 5192

South Asian (SAS) AF: 0.233 AC: 1124 AN: 4820

European-Finnish (FIN) AF: 0.239 AC: 2530 AN: 10578

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16256 AN: 67954

Other (OTH) AF: 0.235 AC: 496 AN: 2110

Alfa AF: 0.246 Hom.: 7412

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

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Primary ciliary dyskinesia Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 10, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 provided Benign:2

Dec 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.8
DANN	Benign	0.86
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10057007; hg19: chr5-13882841;