rs72655972

Positions:

• chr7-21558882-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001277115.2(DNAH11):​c.576A>G​(p.Ile192Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,608,060 control chromosomes in the GnomAD database, including 555 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I192K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (58 hom., cov: 33)
  • Exomes 𝑓: 0.010 (497 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.95

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017288923).
• BP6: Variant 7-21558882-A-G is Benign according to our data. Variant chr7-21558882-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 163094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.576A>G	p.Ile192Met	missense_variant	3/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.576A>G	p.Ile192Met	missense_variant	3/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1825 AN: 152230 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.0573

Gnomad SAS AF: 0.0809

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00260

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0256 AC: 6106 AN: 238600 Hom.: 207 AF XY: 0.0262 AC XY: 3387 AN XY: 129100

Gnomad AFR exome AF: 0.00219

Gnomad AMR exome AF: 0.0648

Gnomad ASJ exome AF: 0.0163

Gnomad EAS exome AF: 0.0622

Gnomad SAS exome AF: 0.0788

Gnomad FIN exome AF: 0.000188

Gnomad NFE exome AF: 0.00251

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0102 AC: 14879 AN: 1455712 Hom.: 497 Cov.: 31 AF XY: 0.0119 AC XY: 8617 AN XY: 723494

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.0618

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0506

Gnomad4 SAS exome AF: 0.0748

Gnomad4 FIN exome AF: 0.000358

Gnomad4 NFE exome AF: 0.00213

Gnomad4 OTH exome AF: 0.0152

GnomAD4 genome AF: 0.0120 AC: 1826 AN: 152348 Hom.: 58 Cov.: 33 AF XY: 0.0147 AC XY: 1098 AN XY: 74502

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.0505

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.0573

Gnomad4 SAS AF: 0.0808

Gnomad4 FIN AF: 0.000376

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.00525 Hom.: 25

Bravo AF: 0.0124

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00302 AC: 11

ESP6500EA AF: 0.00429 AC: 35

ExAC AF: 0.0234 AC: 2822

Asia WGS AF: 0.0630 AC: 219 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ile192Met in exon 3 of DNAH11: This variant is not expected to have clinical sig nificance because it has been identified in 7.3% (13/178) of Japanese chromosome s from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.g ov/projects/SNP; dbSNP rs72655972). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.97
Eigen	Benign	0.068
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N
PrimateAI	Benign	0.27	T
Polyphen		0.66	.;.;P
Vest4		0.049
ClinPred		0.020	T
GERP RS		4.9
Varity_R		0.073
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs72655972; hg19: chr7-21598500; COSMIC: COSV100177484; COSMIC: COSV100177484;