rs189821372

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3BP6BS1BS2

The NM_001277115.2(DNAH11):c.8798-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00412 in 1,590,046 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 27 hom. )

Consequence

DNAH11
NM_001277115.2 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9741

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 0.295

Variant links:

Genes affected

DNAH11 (HGNC:2942): (dynein axonemal heavy chain 11) This gene encodes a ciliary outer dynein arm protein and is a member of the dynein heavy chain family. It is a microtubule-dependent motor ATPase and has been reported to be involved in the movement of respiratory cilia. Mutations in this gene have been implicated in causing Kartagener Syndrome (a combination of situs inversus totalis and Primary Ciliary Dyskinesia (PCD), also called Immotile Cilia Syndrome 1 (ICS1)) and male sterility. [provided by RefSeq, Mar 2013]

DNAH11 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_RF.

BP6

Variant 7-21750217-G-A is Benign according to our data. Variant chr7-21750217-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163114.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00316 (481/152138) while in subpopulation SAS AF= 0.0083 (40/4818). AF 95% confidence interval is 0.00627. There are 3 homozygotes in gnomad4. There are 210 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.8798-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8 linkuse as main transcript	c.8798-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

482

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00952

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00850

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00472

Gnomad OTH

AF:

0.00480

GnomAD3 exomes

AF:

0.00391

AC:

868

AN:

221866

Hom.:

AF XY:

0.00420

AC XY:

500

AN XY:

119100

show subpopulations

Gnomad AFR exome

AF:

0.000286

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00819

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00999

Gnomad FIN exome

AF:

0.00227

Gnomad NFE exome

AF:

0.00416

Gnomad OTH exome

AF:

0.00453

GnomAD4 exome

AF:

0.00422

AC:

6069

AN:

1437908

Hom.:

Cov.:

AF XY:

0.00447

AC XY:

3188

AN XY:

712654

show subpopulations

Gnomad4 AFR exome

AF:

0.000733

Gnomad4 AMR exome

AF:

0.00173

Gnomad4 ASJ exome

AF:

0.00937

Gnomad4 EAS exome

AF:

0.0000255

Gnomad4 SAS exome

AF:

0.0102

Gnomad4 FIN exome

AF:

0.00265

Gnomad4 NFE exome

AF:

0.00408

Gnomad4 OTH exome

AF:

0.00434

GnomAD4 genome

AF:

0.00316

AC:

481

AN:

152138

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

210

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000795

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00952

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00830

Gnomad4 FIN

AF:

0.00104

Gnomad4 NFE

AF:

0.00472

Gnomad4 OTH

AF:

0.00475

Alfa

AF:

0.00410

Hom.:

Bravo

AF:

0.00291

Asia WGS

AF:

0.00462

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	8798-5G>A in intron 53 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 0.4% (34/8186) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs189821372). -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 03, 2023

The DNAH11 c.8798-5G>A variant (rs189821372) is reported in the literature in an individual affected with primary ciliary dyskinesia who harbored another DNAH11 variant (c.3544C>T; p.Arg1182Ter) in trans (Shoemark 2018). The c.8798-5G>A variant is reported in ClinVar (Variation ID: 163114) and is found in the general population with an overall allele frequency of 0.3759% (952/253,256 alleles, including 9 homozygotes) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. However, the splicing impact of this variant would need to be determined by functional studies. Due to limited information, the clinical significance of this variant is uncertain at this time. References: Shoemark A et al C. Primary ciliary dyskinesia with normal ultrastructure: three-dimensional tomography detects absence of DNAH11. Eur Respir J. 2018 Feb 21;51(2):1701809. PMID: 29467202. -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2022

DNAH11: PP3, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Benign

0.68

SpliceAI score (max)

0.63

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.63

Position offset: 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