rs145645790

Variant names:

• chr7-21789325-A-C
• rs145645790
• NM_001277115.2:c.10009A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-21789325-A-C
• chr7-21789325-A-G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001277115.2(DNAH11):​c.10009A>C​(p.Ile3337Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000564 in 1,417,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3337V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

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]

DNAH11 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 7

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15606427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.10009A>C	p.Ile3337Leu	missense_variant	Exon 61 of 82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.10009A>C	p.Ile3337Leu	missense_variant	Exon 61 of 82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1417256 Hom.: 0 Cov.: 30 AF XY: 0.00000285 AC XY: 2 AN XY: 700606

African (AFR) AF: 0.00 AC: 0 AN: 32322

American (AMR) AF: 0.00 AC: 0 AN: 38074

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25334

East Asian (EAS) AF: 0.00 AC: 0 AN: 37388

South Asian (SAS) AF: 0.00 AC: 0 AN: 79918

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50790

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00000735 AC: 8 AN: 1088834

Other (OTH) AF: 0.00 AC: 0 AN: 58886

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 11, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Ile3337Leu vari ant in DNAH11 has not been previously identified in individuals with pulmonary d isease or in large population studies. Isoleucine (Ile) at position 3337 is poor ly conserved in evolution and at least 1 mammal (armadillo) carries the variant amino acid, raising the possibility that this change may be tolerated. Additiona l computational analyses (biochemical amino acid properties, AlignGVGD, PolyPhen 2, and SIFT) also suggest that this variant may not impact the protein, though t his information is not predictive enough to rule out pathogenicity. In summary, the lack of evolutionary conservation suggests that this variant may be more lik ely benign, but additional information is needed to fully assess its clinical si gnificance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.064	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.26	.;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.71	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.88	T
PhyloP100		1.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.7	.;N;.
REVEL	Benign	0.19
Sift	Benign	0.41	.;T;.
Vest4		0.30
MutPred		0.50		Gain of disorder (P = 0.0405);Gain of disorder (P = 0.0405);.;
MVP		0.38
ClinPred		0.24	T
GERP RS		1.1
Varity_R		0.19
gMVP		0.26
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs145645790; hg19: chr7-21828943;