rs12670130

chr7-21588579-A-Gchr7-21588579-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.1916A>G(p.Gln639Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 1,612,248 control chromosomes in the GnomAD database, including 21,350 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q639W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (1762 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19588 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.88

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=0.0027352571).
• BP6: Variant 7-21588579-A-G is Benign according to our data. Variant chr7-21588579-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21588579-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.1916A>G	p.Gln639Arg	missense_variant	11/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.1916A>G	p.Gln639Arg	missense_variant	11/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23006 AN: 152146 Hom.: 1762 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.126

Gnomad ASJ AF: 0.194

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.128

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.174

GnomAD3 exomes AF: 0.146 AC: 36443 AN: 248812 Hom.: 2909 AF XY: 0.149 AC XY: 20115 AN XY: 134988

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0817

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.198

Gnomad SAS exome AF: 0.126

Gnomad FIN exome AF: 0.123

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.161 AC: 235078 AN: 1459984 Hom.: 19588 Cov.: 32 AF XY: 0.160 AC XY: 116533 AN XY: 726350

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.0880

Gnomad4 ASJ exome AF: 0.190

Gnomad4 EAS exome AF: 0.161

Gnomad4 SAS exome AF: 0.127

Gnomad4 FIN exome AF: 0.125

Gnomad4 NFE exome AF: 0.168

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome AF: 0.151 AC: 23008 AN: 152264 Hom.: 1762 Cov.: 33 AF XY: 0.148 AC XY: 11011 AN XY: 74438

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.194

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.122

Gnomad4 FIN AF: 0.128

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.170

Alfa AF: 0.163 Hom.: 4410

Bravo AF: 0.152

TwinsUK AF: 0.182 AC: 675

ALSPAC AF: 0.165 AC: 634

ESP6500AA AF: 0.126 AC: 469

ESP6500EA AF: 0.169 AC: 1393

ExAC AF: 0.149 AC: 17988

Asia WGS AF: 0.129 AC: 449 AN: 3478

EpiCase AF: 0.176

EpiControl AF: 0.177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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	Gln639Arg in exon 11 of DNAH11: This variant is not expected to have clinical si gnificance because it has been identified in 16.9% (1393/8222) of European Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs12670130). -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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

Jan 21, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	8.8
Dann	Benign	0.23
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.36	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.21	T
Polyphen		0.0	.;.;B
Vest4		0.012
ClinPred		0.00042	T
GERP RS		0.13
Varity_R		0.045
gMVP		0.16

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: rs12670130; hg19: chr7-21628197; COSMIC: COSV60959928;