rs182389910

chr7-21861883-G-Achr7-21861883-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):c.11233G>A(p.Glu3745Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,613,246 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (16 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (36 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.12

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005862832).
• BP6: Variant 7-21861883-G-A is Benign according to our data. Variant chr7-21861883-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226579.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}. Variant chr7-21861883-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00438 (666/152140) while in subpopulation AMR AF= 0.0308 (471/15282). AF 95% confidence interval is 0.0285. There are 16 homozygotes in gnomad4. There are 392 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.11233G>A	p.Glu3745Lys	missense_variant	69/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.11233G>A	p.Glu3745Lys	missense_variant	69/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1	n.416G>A		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5	n.496G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152022 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.000846

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00569 AC: 1410 AN: 247996 Hom.: 31 AF XY: 0.00467 AC XY: 629 AN XY: 134564

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000459

Gnomad FIN exome AF: 0.00297

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00617

GnomAD4 exome AF: 0.00266 AC: 3891 AN: 1461106 Hom.: 36 Cov.: 30 AF XY: 0.00241 AC XY: 1753 AN XY: 726832

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.00347

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00227

GnomAD4 genome AF: 0.00438 AC: 666 AN: 152140 Hom.: 16 Cov.: 33 AF XY: 0.00527 AC XY: 392 AN XY: 74380

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.0308

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00198

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00131 Hom.: 2

Bravo AF: 0.00576

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000246 AC: 1

ESP6500EA AF: 0.00227 AC: 19

ExAC AF: 0.00422 AC: 511

EpiCase AF: 0.00158

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 03, 2016	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 10, 2021	This variant is associated with the following publications: (PMID: 31213628) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 16, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 16, 2015

p.Glu3745Lys in exon 69 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 3.0% (360/11530), including 10 h omozygotes, of Latino chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org; dbSNP rs182389910). -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	17
Dann	Benign	0.83
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.66	T;T;T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
Vest4		0.46
MVP		0.38
ClinPred		0.017	T
GERP RS		-0.00051
Varity_R		0.056
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs182389910; hg19: chr7-21901501;