rs6461613

chr7-21884396-A-Gchr7-21884396-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):c.12493A>G(p.Met4165Val) variant causes a missense change. The variant allele was found at a frequency of 0.802 in 1,608,656 control chromosomes in the GnomAD database, including 528,502 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (39739 hom., cov: 32)
  • Exomes 𝑓: 0.81 (488763 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.69

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.890553E-7).
• BP6: Variant 7-21884396-A-G is Benign according to our data. Variant chr7-21884396-A-G is described in ClinVar as [Benign]. Clinvar id is 178735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21884396-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.832 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.12493A>G	p.Met4165Val	missense_variant	76/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.12493A>G	p.Met4165Val	missense_variant	76/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.695 AC: 105726 AN: 152060 Hom.: 39737 Cov.: 32

Gnomad AFR AF: 0.399

Gnomad AMI AF: 0.903

Gnomad AMR AF: 0.690

Gnomad ASJ AF: 0.819

Gnomad EAS AF: 0.663

Gnomad SAS AF: 0.743

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.728

GnomAD3 exomes AF: 0.756 AC: 185702 AN: 245538 Hom.: 72568 AF XY: 0.769 AC XY: 102429 AN XY: 133148

Gnomad AFR exome AF: 0.392

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.685

Gnomad SAS exome AF: 0.745

Gnomad FIN exome AF: 0.862

Gnomad NFE exome AF: 0.840

Gnomad OTH exome AF: 0.787

GnomAD4 exome AF: 0.814 AC: 1185018 AN: 1456478 Hom.: 488763 Cov.: 40 AF XY: 0.813 AC XY: 589095 AN XY: 724356

Gnomad4 AFR exome AF: 0.379

Gnomad4 AMR exome AF: 0.608

Gnomad4 ASJ exome AF: 0.828

Gnomad4 EAS exome AF: 0.608

Gnomad4 SAS exome AF: 0.749

Gnomad4 FIN exome AF: 0.863

Gnomad4 NFE exome AF: 0.846

Gnomad4 OTH exome AF: 0.793

GnomAD4 genome AF: 0.695 AC: 105751 AN: 152178 Hom.: 39739 Cov.: 32 AF XY: 0.696 AC XY: 51762 AN XY: 74394

Gnomad4 AFR AF: 0.399

Gnomad4 AMR AF: 0.689

Gnomad4 ASJ AF: 0.819

Gnomad4 EAS AF: 0.662

Gnomad4 SAS AF: 0.743

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.837

Gnomad4 OTH AF: 0.728

Alfa AF: 0.779 Hom.: 22253

Bravo AF: 0.666

TwinsUK AF: 0.854 AC: 3168

ALSPAC AF: 0.848 AC: 3270

ESP6500AA AF: 0.440 AC: 1752

ESP6500EA AF: 0.848 AC: 7150

ExAC AF: 0.755 AC: 91244

Asia WGS AF: 0.673 AC: 2342 AN: 3478

EpiCase AF: 0.841

EpiControl AF: 0.839

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Met4165Val in exon 76 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 44.0% (1752/3986) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs6461613). -
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	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	20
Dann	Benign	0.96
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.59	T;T;T
MetaRNN	Benign	8.9e-7	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.00021	P
PrimateAI	Benign	0.44	T
Vest4		0.11
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.65
gMVP		0.37

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

Other links and lift over

dbSNP: rs6461613; hg19: chr7-21924014; COSMIC: COSV60943924;