rs72657371

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001277115.2(DNAH11):c.8969G>A(p.Arg2990His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,613,676 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.014 ( 36 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 58 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.691

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037251115).

BP6

Variant 7-21765456-G-A is Benign according to our data. Variant chr7-21765456-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 238937.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0137 (2080/152172) while in subpopulation AFR AF= 0.0481 (1994/41494). AF 95% confidence interval is 0.0463. There are 36 homozygotes in gnomad4. There are 993 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.8969G>A	p.Arg2990His	missense_variant	55/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8 linkuse as main transcript	c.8969G>A	p.Arg2990His	missense_variant	55/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes

AF:

0.0136

AC:

2062

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0478

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00413

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00348

AC:

867

AN:

248912

Hom.:

AF XY:

0.00269

AC XY:

363

AN XY:

135018

show subpopulations

Gnomad AFR exome

AF:

0.0483

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000887

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.00141

AC:

2068

AN:

1461504

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

872

AN XY:

727020

show subpopulations

Gnomad4 AFR exome

AF:

0.0505

Gnomad4 AMR exome

AF:

0.00286

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000468

Gnomad4 OTH exome

AF:

0.00303

GnomAD4 genome

AF:

0.0137

AC:

2080

AN:

152172

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

993

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0481

Gnomad4 AMR

AF:

0.00412

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000416

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00617

Hom.:

Bravo

AF:

0.0153

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0464

AC:

189

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00435

AC:

526

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2017	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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2023	See Variant Classification Assertion Criteria. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 27, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Primary ciliary dyskinesia 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.053

.;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.32

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.56

T;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.43

PROVEAN

Benign

2.1

.;N;.

REVEL

Benign

0.029

Sift

Benign

0.32

.;T;.

Vest4

0.21

MVP

0.27

ClinPred

0.031

GERP RS

3.3

Varity_R

0.060

gMVP

0.063

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