rs28751578

Positions:

• chr7-21765585-T-C

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.9098T>C​(p.Ile3033Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00311 in 1,576,640 control chromosomes in the GnomAD database, including 151 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 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. I3033V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (71 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (80 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.84

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=0.003173232).
• BP6: Variant 7-21765585-T-C is Benign according to our data. Variant chr7-21765585-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 238940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.9098T>C	p.Ile3033Thr	missense_variant	55/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.9098T>C	p.Ile3033Thr	missense_variant	55/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0162 AC: 2389 AN: 147518 Hom.: 71 Cov.: 31

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00461

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000659

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00325

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00388 AC: 928 AN: 239040 Hom.: 23 AF XY: 0.00318 AC XY: 413 AN XY: 129836

Gnomad AFR exome AF: 0.0551

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad SAS exome AF: 0.000235

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000837

Gnomad OTH exome AF: 0.00170

GnomAD4 exome AF: 0.00175 AC: 2500 AN: 1428996 Hom.: 80 Cov.: 31 AF XY: 0.00149 AC XY: 1059 AN XY: 710008

Gnomad4 AFR exome AF: 0.0643

Gnomad4 AMR exome AF: 0.00238

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.00398

GnomAD4 genome AF: 0.0163 AC: 2400 AN: 147644 Hom.: 71 Cov.: 31 AF XY: 0.0161 AC XY: 1154 AN XY: 71676

Gnomad4 AFR AF: 0.0568

Gnomad4 AMR AF: 0.00461

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000659

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000149

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00830 Hom.: 14

Bravo AF: 0.0182

ESP6500AA AF: 0.0521 AC: 217

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00512 AC: 619

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 17, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.69	T;T;T
MetaRNN	Benign	0.0032	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.8	.;D;.
REVEL	Benign	0.087
Sift	Uncertain	0.021	.;D;.
Vest4		0.34
MVP		0.42
ClinPred		0.027	T
GERP RS		4.5
Varity_R		0.17
gMVP		0.21

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: rs28751578; hg19: chr7-21805203;