5-13902136-G-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

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. 13/22 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 (★★).

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 33)

Exomes 𝑓: 0.015 ( 169 hom. )

Consequence

DNAH5
NM_001369.3 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.451

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PP3

Splicing scoreres supports a deletorius 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 [Likely_benign]. Clinvar id is 178756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13902136-G-C is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH5	NM_001369.3 link	c.1647C>G	p.Asn549Lys	missense_variant, splice_region_variant	Exon 13 of 79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 link	c.1647C>G	p.Asn549Lys	missense_variant, splice_region_variant	Exon 13 of 79	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 link	c.1602C>G	p.Asn534Lys	missense_variant, splice_region_variant	Exon 13 of 79			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1614

AN:

152102

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0103

AC:

2494

AN:

241900

Hom.:

AF XY:

0.0104

AC XY:

1356

AN XY:

130676

show subpopulations

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 SAS exome

AF:

0.00307

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.:

AF XY:

0.0146

AC XY:

10481

AN XY:

719972

show subpopulations

Gnomad4 AFR exome

AF:

0.00252

Gnomad4 AMR exome

AF:

0.00884

Gnomad4 ASJ exome

AF:

0.0300

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00342

Gnomad4 FIN exome

AF:

0.00263

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0106

AC:

1613

AN:

152220

Hom.:

Cov.:

AF XY:

0.00961

AC XY:

715

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00318

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.0282

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.00208

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.0145

Hom.:

Bravo

AF:

0.0111

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0153

AC:

ESP6500AA

AF:

0.00432

AC:

ESP6500EA

AF:

0.0159

AC:

136

ExAC

AF:

0.00973

AC:

1180

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -

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

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

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). -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 19, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.070

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Benign

0.92

Polyphen

0.0

Vest4

0.13

MutPred

0.51

Gain of ubiquitination at N549 (P = 0.0337);

MPC

0.44

ClinPred

0.013

GERP RS

-1.1

Varity_R

0.11

gMVP

0.25

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over