chr7-21842591-G-A

Position:

chr7-21842591-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001277115.2(DNAH11):c.10739G>A(p.Arg3580His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0138 in 1,613,800 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3580C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 10 hom., cov: 32)

Exomes 𝑓: 0.014 ( 174 hom. )

Consequence

DNAH11
NM_001277115.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.52

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012826085).

BP6

Variant 7-21842591-G-A is Benign according to our data. Variant chr7-21842591-G-A is described in ClinVar as [Benign]. Clinvar id is 178733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00926 (1409/152224) while in subpopulation NFE AF= 0.0152 (1036/68012). AF 95% confidence interval is 0.0145. There are 10 homozygotes in gnomad4. There are 670 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2 linkuse as main transcript	c.10739G>A	p.Arg3580His	missense_variant	66/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8 linkuse as main transcript	c.10739G>A	p.Arg3580His	missense_variant	66/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes

AF:

0.00926

AC:

1408

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00316

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00812

Gnomad ASJ

AF:

0.00923

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00559

Gnomad FIN

AF:

0.00311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00873

AC:

2175

AN:

249044

Hom.:

AF XY:

0.00858

AC XY:

1160

AN XY:

135124

show subpopulations

Gnomad AFR exome

AF:

0.00368

Gnomad AMR exome

AF:

0.00443

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00431

Gnomad FIN exome

AF:

0.00339

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.00993

GnomAD4 exome

AF:

0.0143

AC:

20876

AN:

1461576

Hom.:

174

Cov.:

AF XY:

0.0139

AC XY:

10114

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00284

Gnomad4 AMR exome

AF:

0.00458

Gnomad4 ASJ exome

AF:

0.0106

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00413

Gnomad4 FIN exome

AF:

0.00365

Gnomad4 NFE exome

AF:

0.0170

Gnomad4 OTH exome

AF:

0.0132

GnomAD4 genome

AF:

0.00926

AC:

1409

AN:

152224

Hom.:

Cov.:

AF XY:

0.00900

AC XY:

670

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.00315

Gnomad4 AMR

AF:

0.00811

Gnomad4 ASJ

AF:

0.00923

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00581

Gnomad4 FIN

AF:

0.00311

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.00881

TwinsUK

AF:

0.0194

AC:

ALSPAC

AF:

0.0148

AC:

ESP6500AA

AF:

0.00451

AC:

ESP6500EA

AF:

0.0148

AC:

122

ExAC

AF:

0.00848

AC:

1025

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0145

EpiControl

AF:

0.0120

ClinVar

Significance: Benign

Submissions summary: Benign:8

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg3580His in exon 66 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 1.5% (122/8230) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs34879202). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 01, 2017	- -

Primary ciliary dyskinesia 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 26, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 13, 2022	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	DNAH11: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2020	This variant is associated with the following publications: (PMID: 27637300, 24450482) -

Primary ciliary dyskinesia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

.;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.96

D;D;D

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.66

MutationTaster

Benign

1.0

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-4.7

.;D;.

REVEL

Uncertain

0.30

Sift

Uncertain

0.023

.;D;.

Vest4

0.79

MVP

0.36

ClinPred

0.020

GERP RS

5.4

Varity_R

0.32

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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