chr5-13902136-G-C

Variant names:

• chr5-13902136-G-C
• rs139160176
• NM_001369.3:c.1647C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PP3_Moderate BP6_Very_Strong BS1 BS2

The NM_001369.3(DNAH5):​c.1647C>G​(p.Asn549Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,599,012 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N549N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (17 hom., cov: 33)
  • Exomes 𝑓: 0.015 (169 hom.)
• Consequence: DNAH5 NM_001369.3 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.451
• Publications: 12 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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 5-13902136-G-C is Benign according to our data. Variant chr5-13902136-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 178756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0106 (1613/152220) while in subpopulation NFE AF = 0.016 (1088/68002). AF 95% confidence interval is 0.0152. There are 17 homozygotes in GnomAd4. There are 715 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

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.1647C>G	p.Asn549Lys	missense splice_region	Exon 13 of 79	NP_001360.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DNAH5	ENST00000265104.5	TSL:1 MANE Select	c.1647C>G	p.Asn549Lys	missense splice_region	Exon 13 of 79	ENSP00000265104.4
	DNAH5	ENST00000681290.1		c.1602C>G	p.Asn534Lys	missense splice_region	Exon 13 of 79	ENSP00000505288.1

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1614 AN: 152102 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00319

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.0282

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00310

Gnomad FIN AF: 0.00208

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0103 AC: 2494 AN: 241900 AF XY: 0.0104

Gnomad AFR exome AF: 0.00243

Gnomad AMR exome AF: 0.00842

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00246

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0148 AC: 21380 AN: 1446792 Hom.: 169 Cov.: 28 AF XY: 0.0146 AC XY: 10481 AN XY: 719972

African (AFR) AF: 0.00252 AC: 84 AN: 33314

American (AMR) AF: 0.00884 AC: 392 AN: 44342

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 774 AN: 25770

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39496

South Asian (SAS) AF: 0.00342 AC: 292 AN: 85336

European-Finnish (FIN) AF: 0.00263 AC: 138 AN: 52390

Middle Eastern (MID) AF: 0.0105 AC: 60 AN: 5734

European-Non Finnish (NFE) AF: 0.0170 AC: 18724 AN: 1100556

Other (OTH) AF: 0.0153 AC: 915 AN: 59854

GnomAD4 genome AF: 0.0106 AC: 1613 AN: 152220 Hom.: 17 Cov.: 33 AF XY: 0.00961 AC XY: 715 AN XY: 74418

African (AFR) AF: 0.00318 AC: 132 AN: 41530

American (AMR) AF: 0.0105 AC: 160 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0282 AC: 98 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4830

European-Finnish (FIN) AF: 0.00208 AC: 22 AN: 10588

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0160 AC: 1088 AN: 68002

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0145 Hom.: 10

Bravo AF: 0.0111

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00432 AC: 19

ESP6500EA AF: 0.0159 AC: 136

ExAC AF: 0.00973 AC: 1180

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Dec 11, 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

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:2

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Asn549Lys in exon 13 of DNAH5: This variant is not expected to have clinical sig nificance because it has been identified in 1.6% (136/8580) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs139160176).

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jan 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Primary ciliary dyskinesia 3 Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Mar 06, 2017

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Benign	0.72
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.45
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.11
Sift	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.51		Gain of ubiquitination at N549 (P = 0.0337)
MPC		0.44
ClinPred		0.013	T
GERP RS		-1.1
Varity_R		0.11
gMVP		0.25
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs139160176; hg19: chr5-13902245; COSMIC: COSV108081140; COSMIC: COSV108081140;