rs72657373

chr7-21765584-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.9097A>G(p.Ile3033Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00571 in 1,458,502 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict 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. I3033T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (56 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.37

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=0.0049520135).
• BP6: Variant 7-21765584-A-G is Benign according to our data. Variant chr7-21765584-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163117.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00444 (644/145078) while in subpopulation AMR AF= 0.0201 (290/14456). AF 95% confidence interval is 0.0182. There are 7 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.9097A>G	p.Ile3033Val	missense_variant	55/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.9097A>G	p.Ile3033Val	missense_variant	55/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 642 AN: 144930 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0103

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000408

Gnomad SAS AF: 0.00491

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00401

Gnomad OTH AF: 0.00691

GnomAD3 exomes AF: 0.00680 AC: 1637 AN: 240568 Hom.: 23 AF XY: 0.00625 AC XY: 816 AN XY: 130622

Gnomad AFR exome AF: 0.000527

Gnomad AMR exome AF: 0.0299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad SAS exome AF: 0.00638

Gnomad FIN exome AF: 0.000298

Gnomad NFE exome AF: 0.00352

Gnomad OTH exome AF: 0.00626

GnomAD4 exome AF: 0.00585 AC: 7680 AN: 1313424 Hom.: 56 Cov.: 31 AF XY: 0.00577 AC XY: 3757 AN XY: 651454

Gnomad4 AFR exome AF: 0.000869

Gnomad4 AMR exome AF: 0.0320

Gnomad4 ASJ exome AF: 0.000100

Gnomad4 EAS exome AF: 0.0000557

Gnomad4 SAS exome AF: 0.00715

Gnomad4 FIN exome AF: 0.000582

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00584

GnomAD4 genome AF: 0.00444 AC: 644 AN: 145078 Hom.: 7 Cov.: 31 AF XY: 0.00453 AC XY: 319 AN XY: 70436

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.0201

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000409

Gnomad4 SAS AF: 0.00514

Gnomad4 FIN AF: 0.000328

Gnomad4 NFE AF: 0.00401

Gnomad4 OTH AF: 0.00683

Alfa AF: 0.00342 Hom.: 2

Bravo AF: 0.00593

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000480 AC: 2

ESP6500EA AF: 0.00344 AC: 29

ExAC AF: 0.00581 AC: 703

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 03, 2015	p.Ile3033Val in exon 55 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 3.6% (373/10238) of Latino chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs72657373). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 06, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 24, 2020

This variant is associated with the following publications: (PMID: 18492703, 31213628) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
Cadd	Benign	18
Dann	Uncertain	0.98
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.64	T;T;T
MetaRNN	Benign	0.0050	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.80	D
PrimateAI	Benign	0.29	T
Vest4		0.37
MVP		0.38
ClinPred		0.018	T
GERP RS		4.5
Varity_R		0.040
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs72657373; hg19: chr7-21805202;