rs189432084

Positions:

• chr7-21658835-A-G

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.5132A>G​(p.Gln1711Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,600,310 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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 0.00032 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (3 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 0.471

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=0.0073883235).
• BP6: Variant 7-21658835-A-G is Benign according to our data. Variant chr7-21658835-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 219477.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}. Variant chr7-21658835-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000462 (669/1448072) while in subpopulation MID AF= 0.0108 (62/5744). AF 95% confidence interval is 0.00864. There are 3 homozygotes in gnomad4_exome. There are 346 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• 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.5132A>G	p.Gln1711Arg	missense_variant	30/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.5132A>G	p.Gln1711Arg	missense_variant	30/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000531 AC: 121 AN: 228082 Hom.: 0 AF XY: 0.000577 AC XY: 71 AN XY: 122958

Gnomad AFR exome AF: 0.0000717

Gnomad AMR exome AF: 0.000656

Gnomad ASJ exome AF: 0.000838

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000325

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000714

Gnomad OTH exome AF: 0.00160

GnomAD4 exome AF: 0.000462 AC: 669 AN: 1448072 Hom.: 3 Cov.: 31 AF XY: 0.000481 AC XY: 346 AN XY: 718790

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.000800

Gnomad4 ASJ exome AF: 0.000737

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000442

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000384

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152238 Hom.: 0 Cov.: 31 AF XY: 0.000269 AC XY: 20 AN XY: 74440

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000622 Hom.: 1

Bravo AF: 0.000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000975 AC: 8

ExAC AF: 0.000606 AC: 73

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 12, 2015	This alteration is classified as benign based on a combination of the following: 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

DNAH11-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

The DNAH11 c.5132A>G variant is predicted to result in the amino acid substitution p.Gln1711Arg. This variant has been reported along with additional DNAH11 variants in individuals with primary ciliary dyskinesia (Table 4, Sherman et al. 2020. PubMed ID: 32662935; Alsamri et al. 2021. PubMed ID: 34768622). This variant is reported in 0.081% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 03, 2017

p.Gln1711Arg in exon 30 of DNAH11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, shrew, tenrec, and platypus have an arginine (Arg) at this position desp ite high nearby amino acid conservation. In addition, computational prediction t ools do not suggest a high likelihood of impact to the protein. It has also been identified in 0.2% (48/26256) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs189432084). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.2
DANN	Benign	0.17
DEOGEN2	Benign	0.068	.;.;T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.69	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.99	.;N;.
REVEL	Benign	0.072
Sift	Benign	1.0	.;T;.
Vest4		0.21
MVP		0.35
ClinPred		0.0080	T
GERP RS		2.4
Varity_R		0.091
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs189432084; hg19: chr7-21698453;