rs189569144

Positions:

• chr7-21599943-C-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001277115.2(DNAH11):​c.2824C>A​(p.Pro942Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000248 in 1,613,464 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).

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.71

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05141291).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.2824C>A	p.Pro942Thr	missense_variant	15/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.2824C>A	p.Pro942Thr	missense_variant	15/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151934 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000503 AC: 125 AN: 248476 Hom.: 0 AF XY: 0.000542 AC XY: 73 AN XY: 134800

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.00289

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.00193

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000829

GnomAD4 exome AF: 0.000249 AC: 364 AN: 1461408 Hom.: 3 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 726960

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00276

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000711

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000237 AC: 36 AN: 152056 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74346

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000232 Hom.: 0

Bravo AF: 0.000170

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000472 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Dec 11, 2023	This sequence change replaces proline with threonine at evolutionary conserved position 942 of the DNAH11 protein (p.Pro942Thr). The c.2824C>A has a low allele frequency in gnomAD Genomes (Version 3.1.2: ƒ = 0.000237) and several ClinVar submissions with conflicting interpretations of pathogenicity (variation ID 359618). The patient possessed the c.2824C>A variant in trans with another rare missense variant in DNAH11 (c.2966G>A, p.Arg989Gln). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2017	The p.P942T variant (also known as c.2824C>A), located in coding exon 15 of the DNAH11 gene, results from a C to A substitution at nucleotide position 2824. The proline at codon 942 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	DNAH11: PM2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;.;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.2	.;.;M
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-6.8	.;D;.
REVEL	Uncertain	0.43
Sift	Benign	0.047	.;D;.
Polyphen		1.0	.;.;D
Vest4		0.54
MVP		0.39
ClinPred		0.20	T
GERP RS		5.6
Varity_R		0.24
gMVP		0.56

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: rs189569144; hg19: chr7-21639561;