rs77541151

Variant summary

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

The NM_001369.3(DNAH5):c.12033+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,611,672 control chromosomes in the GnomAD database, including 248 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 130 hom., cov: 33)

Exomes 𝑓: 0.0022 ( 118 hom. )

Consequence

DNAH5
NM_001369.3 splice_region, intron

Scores

Splicing: ADA: 0.00009990

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.393

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 (BayesDel_noAF=-0.83).

BP6

Variant 5-13727500-T-C is Benign according to our data. Variant chr5-13727500-T-C is described in ClinVar as [Benign]. Clinvar id is 226591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-13727500-T-C is described in Lovd as [Benign]. Variant chr5-13727500-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0725 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3 linkuse as main transcript	c.12033+7A>G		splice_region_variant, intron_variant		ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5 linkuse as main transcript	c.12033+7A>G		splice_region_variant, intron_variant		1	NM_001369.3	P4
DNAH5	ENST00000681290.1 linkuse as main transcript	c.11988+7A>G		splice_region_variant, intron_variant				A1

Frequencies

GnomAD3 genomes

AF:

0.0215

AC:

3273

AN:

152158

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00766

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.0177

GnomAD3 exomes

AF:

0.00556

AC:

1391

AN:

250122

Hom.:

AF XY:

0.00425

AC XY:

576

AN XY:

135424

show subpopulations

Gnomad AFR exome

AF:

0.0771

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000426

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00221

AC:

3222

AN:

1459396

Hom.:

118

Cov.:

AF XY:

0.00199

AC XY:

1447

AN XY:

726054

show subpopulations

Gnomad4 AFR exome

AF:

0.0765

Gnomad4 AMR exome

AF:

0.00428

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000396

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000901

Gnomad4 OTH exome

AF:

0.00526

GnomAD4 genome

AF:

0.0215

AC:

3276

AN:

152276

Hom.:

130

Cov.:

AF XY:

0.0207

AC XY:

1540

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0747

Gnomad4 AMR

AF:

0.00765

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.0176

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.0244

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	12033+7A>G in intron 70 of DNAH5: This variant is not expected to have clinical significance because it is not located within the conserved splice consensus seq uence. It has been identified in 7.5% (330/4404) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.wa shington.edu/EVS; dbSNP rs77541151). -

Primary ciliary dyskinesia 3

Benign:3

Benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Primary ciliary dyskinesia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

Cadd

Benign

0.45

Dann

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00010

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.060

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