chr5-13894785-T-A

Variant names:

• chr5-13894785-T-A
• rs4701997
• NM_001369.3:c.2296A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001369.3(DNAH5):​c.2296A>T​(p.Ile766Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,613,488 control chromosomes in the GnomAD database, including 211,044 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I766M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.50 (19427 hom., cov: 32)
  • Exomes 𝑓: 0.51 (191617 hom.)
• Consequence: DNAH5 NM_001369.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 3.01
• Publications: 33 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2438915E-5).
• BP6: Variant 5-13894785-T-A is Benign according to our data. Variant chr5-13894785-T-A is described in CliVar as Benign. Clinvar id is 178753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13894785-T-A is described in CliVar as Benign. Clinvar id is 178753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13894785-T-A is described in CliVar as Benign. Clinvar id is 178753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3	c.2296A>T	p.Ile766Leu	missense_variant	Exon 16 of 79	ENST00000265104.5	NP_001360.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5	c.2296A>T	p.Ile766Leu	missense_variant	Exon 16 of 79	1	NM_001369.3	ENSP00000265104.4
DNAH5	ENST00000681290.1	c.2251A>T	p.Ile751Leu	missense_variant	Exon 16 of 79			ENSP00000505288.1
ENSG00000251423	ENST00000503244.2	n.254-1804T>A		intron_variant	Intron 1 of 2	4
ENSG00000251423	ENST00000637153.1	n.214-1804T>A		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.504 AC: 76485 AN: 151852 Hom.: 19411 Cov.: 32

Gnomad AFR AF: 0.530

Gnomad AMI AF: 0.524

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.527

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.449

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.508

Gnomad OTH AF: 0.506

GnomAD2 exomes AF: 0.500 AC: 125490 AN: 251066 AF XY: 0.508

Gnomad AFR exome AF: 0.534

Gnomad AMR exome AF: 0.497

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.509

Gnomad OTH exome AF: 0.495

GnomAD4 exome AF: 0.509 AC: 743312 AN: 1461518 Hom.: 191617 Cov.: 54 AF XY: 0.512 AC XY: 372466 AN XY: 727080

African (AFR) AF: 0.538 AC: 17993 AN: 33472

American (AMR) AF: 0.497 AC: 22227 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 13660 AN: 26128

East Asian (EAS) AF: 0.242 AC: 9617 AN: 39688

South Asian (SAS) AF: 0.625 AC: 53932 AN: 86252

European-Finnish (FIN) AF: 0.457 AC: 24387 AN: 53348

Middle Eastern (MID) AF: 0.541 AC: 3123 AN: 5768

European-Non Finnish (NFE) AF: 0.511 AC: 568128 AN: 1111764

Other (OTH) AF: 0.501 AC: 30245 AN: 60384

GnomAD4 genome AF: 0.504 AC: 76550 AN: 151970 Hom.: 19427 Cov.: 32 AF XY: 0.502 AC XY: 37314 AN XY: 74278

African (AFR) AF: 0.530 AC: 21956 AN: 41456

American (AMR) AF: 0.500 AC: 7632 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.527 AC: 1830 AN: 3470

East Asian (EAS) AF: 0.243 AC: 1257 AN: 5182

South Asian (SAS) AF: 0.609 AC: 2935 AN: 4816

European-Finnish (FIN) AF: 0.449 AC: 4730 AN: 10538

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.508 AC: 34494 AN: 67936

Other (OTH) AF: 0.508 AC: 1068 AN: 2104

Alfa AF: 0.507 Hom.: 14802

Bravo AF: 0.505

TwinsUK AF: 0.509 AC: 1887

ALSPAC AF: 0.528 AC: 2035

ESP6500AA AF: 0.533 AC: 2349

ESP6500EA AF: 0.508 AC: 4368

ExAC AF: 0.507 AC: 61573

Asia WGS AF: 0.453 AC: 1577 AN: 3478

EpiCase AF: 0.510

EpiControl AF: 0.512

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile766Leu in exon 16 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 49.2% (4232/8600) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs4701997). -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Nov 26, 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Primary ciliary dyskinesia 3 Benign:3

Jun 15, 2021

Pars Genome Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.000022	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.088
Sift	Benign	0.31	T
Polyphen		0.0010	B
Vest4		0.088
MutPred		0.44		Gain of ubiquitination at K765 (P = 0.1047);
MPC		0.093
ClinPred		0.027	T
GERP RS		4.4
Varity_R		0.18
gMVP		0.26
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4701997; hg19: chr5-13894894; COSMIC: COSV54204943;