rs17263496

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001369.3(DNAH5):c.11372C>T(p.Thr3791Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,910 control chromosomes in the GnomAD database, including 13,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 1030 hom., cov: 32)

Exomes 𝑓: 0.12 ( 12100 hom. )

Consequence

DNAH5
NM_001369.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.04

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001767695).

BP6

Variant 5-13737335-G-A is Benign according to our data. Variant chr5-13737335-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13737335-G-A is described in Lovd as [Benign]. Variant chr5-13737335-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.11372C>T	p.Thr3791Ile	missense_variant	66/79	ENST00000265104.5	NP_001360.1	Q8TE73

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.11372C>T	p.Thr3791Ile	missense_variant	66/79	1	NM_001369.3	ENSP00000265104.4		Q8TE73
DNAH5	ENST00000681290.1 linkuse as main transcript	c.11327C>T	p.Thr3776Ile	missense_variant	66/79			ENSP00000505288.1		A0A7P0Z455

Frequencies

GnomAD3 genomes

AF:

0.102

AC:

15522

AN:

152022

Hom.:

1030

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0336

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0923

Gnomad ASJ

AF:

0.150

Gnomad EAS

AF:

0.0493

Gnomad SAS

AF:

0.0423

Gnomad FIN

AF:

0.215

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.133

Gnomad OTH

AF:

0.109

GnomAD3 exomes

AF:

0.104

AC:

26255

AN:

251364

Hom.:

1719

AF XY:

0.103

AC XY:

14007

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.0299

Gnomad AMR exome

AF:

0.0619

Gnomad ASJ exome

AF:

0.148

Gnomad EAS exome

AF:

0.0403

Gnomad SAS exome

AF:

0.0378

Gnomad FIN exome

AF:

0.204

Gnomad NFE exome

AF:

0.133

Gnomad OTH exome

AF:

0.116

GnomAD4 exome

AF:

0.123

AC:

179440

AN:

1461770

Hom.:

12100

Cov.:

AF XY:

0.121

AC XY:

87866

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0285

Gnomad4 AMR exome

AF:

0.0658

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.0503

Gnomad4 SAS exome

AF:

0.0377

Gnomad4 FIN exome

AF:

0.198

Gnomad4 NFE exome

AF:

0.134

Gnomad4 OTH exome

AF:

0.111

GnomAD4 genome

AF:

0.102

AC:

15519

AN:

152140

Hom.:

1030

Cov.:

AF XY:

0.104

AC XY:

7719

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0336

Gnomad4 AMR

AF:

0.0921

Gnomad4 ASJ

AF:

0.150

Gnomad4 EAS

AF:

0.0490

Gnomad4 SAS

AF:

0.0425

Gnomad4 FIN

AF:

0.215

Gnomad4 NFE

AF:

0.133

Gnomad4 OTH

AF:

0.109

Alfa

AF:

0.122

Hom.:

2565

Bravo

AF:

0.0910

TwinsUK

AF:

0.137

AC:

509

ALSPAC

AF:

0.139

AC:

536

ESP6500AA

AF:

0.0306

AC:

135

ESP6500EA

AF:

0.127

AC:

1092

ExAC

AF:

0.101

AC:

12283

Asia WGS

AF:

0.0500

AC:

173

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.125

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 11, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr3791Ile in exon 66 of DNAH5: This variant is not expected to have clinical si gnificance because it has been identified in 12.7% (1092/8600) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs17263496). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Primary ciliary dyskinesia 3

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.93

MutationAssessor

Pathogenic

3.4

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Polyphen

0.99

Vest4

0.35

MPC

0.41

ClinPred

0.053

GERP RS

5.4

Varity_R

0.89

gMVP

0.58

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

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