rs370932895

chr7-21816606-G-Achr7-21816606-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP3 BP4_Moderate

The NM_001277115.2(DNAH11):c.10472G>A(p.Arg3491His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,728 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3491C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:1
• Conservation: PhyloP100: 7.88

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 Likely_benign. Variant got -1 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, MetaRNN, MutationTaster, PrimateAI was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.096747965).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.10472G>A	p.Arg3491His	missense_variant	64/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.10472G>A	p.Arg3491His	missense_variant	64/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000647 AC: 161 AN: 248790 Hom.: 0 AF XY: 0.000778 AC XY: 105 AN XY: 134946

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000691

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.000708 AC: 1035 AN: 1461432 Hom.: 3 Cov.: 34 AF XY: 0.000743 AC XY: 540 AN XY: 726966

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00176

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000718

Gnomad4 OTH exome AF: 0.000663

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152296 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74464

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000534 Hom.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000255 AC: 1

ESP6500EA AF: 0.000843 AC: 7

ExAC AF: 0.000720 AC: 87

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000949

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, flagged submission	clinical testing	GeneDx	Aug 29, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30755392, 35586607, 37035737) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 18, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Primary ciliary dyskinesia 7 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 29, 2021	This variant was observed in compound heterozygosity with variant c.1848+1G>T -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 05, 2018	The p.R3491H variant (also known as c.10472G>A), located in coding exon 64 of the DNAH11 gene, results from a G to A substitution at nucleotide position 10472. The arginine at codon 3491 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 23, 2017

proposed classification - variant undergoing re-assessment, contact laboratory -

DNAH11-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

The DNAH11 c.10472G>A variant is predicted to result in the amino acid substitution p.Arg3491His. This variant has been reported in the homozygous state in an individual with skeletal anomalies and cognitive impairment who also carries a homozygous truncating variant in TMCO1 (Ji et al. 2019. PubMed ID: 30755392). This variant is reported in 0.17% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cleft upper lip;C0023529:Periventricular leukomalacia;C0338656:Cognitive impairment;C1850256:Median cleft upper lip;C1858033:Asymmetry of the thorax;C2981150:Cleft palate;C4721788:Bifid ribs Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.097	T;T;T
MetaSVM	Benign	-0.64	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
Vest4		0.70
MVP		0.43
ClinPred		0.19	T
GERP RS		5.5
Varity_R		0.78
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs370932895; hg19: chr7-21856224; COSMIC: COSV60939374;