rs72655988

chr7-21582013-G-Achr7-21582013-G-T

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.1702G>A(p.Ala568Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,603,644 control chromosomes in the GnomAD database, including 1,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (134 hom., cov: 33)
  • Exomes 𝑓: 0.045 (1671 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.48

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=0.0040915906).
• BP6: Variant 7-21582013-G-A is Benign according to our data. Variant chr7-21582013-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21582013-G-A is described in Lovd as [Benign]. Variant chr7-21582013-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.1702G>A	p.Ala568Thr	missense_variant	9/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.1702G>A	p.Ala568Thr	missense_variant	9/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6171 AN: 152154 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.0408

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.0187

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0459

Gnomad OTH AF: 0.0398

GnomAD3 exomes AF: 0.0395 AC: 9788 AN: 247902 Hom.: 245 AF XY: 0.0411 AC XY: 5527 AN XY: 134464

Gnomad AFR exome AF: 0.0390

Gnomad AMR exome AF: 0.0121

Gnomad ASJ exome AF: 0.0462

Gnomad EAS exome AF: 0.0236

Gnomad SAS exome AF: 0.0541

Gnomad FIN exome AF: 0.0350

Gnomad NFE exome AF: 0.0469

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0446 AC: 64676 AN: 1451372 Hom.: 1671 Cov.: 27 AF XY: 0.0450 AC XY: 32494 AN XY: 722518

Gnomad4 AFR exome AF: 0.0415

Gnomad4 AMR exome AF: 0.0135

Gnomad4 ASJ exome AF: 0.0445

Gnomad4 EAS exome AF: 0.0126

Gnomad4 SAS exome AF: 0.0550

Gnomad4 FIN exome AF: 0.0374

Gnomad4 NFE exome AF: 0.0468

Gnomad4 OTH exome AF: 0.0424

GnomAD4 genome AF: 0.0405 AC: 6169 AN: 152272 Hom.: 134 Cov.: 33 AF XY: 0.0399 AC XY: 2974 AN XY: 74460

Gnomad4 AFR AF: 0.0406

Gnomad4 AMR AF: 0.0203

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0459

Gnomad4 OTH AF: 0.0394

Alfa AF: 0.0418 Hom.: 197

Bravo AF: 0.0381

TwinsUK AF: 0.0515 AC: 191

ALSPAC AF: 0.0485 AC: 187

ESP6500AA AF: 0.0401 AC: 145

ESP6500EA AF: 0.0444 AC: 362

ExAC AF: 0.0413 AC: 4984

Asia WGS AF: 0.0410 AC: 142 AN: 3478

EpiCase AF: 0.0410

EpiControl AF: 0.0409

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala568Thr in exon 9 of DNAH11: This variant is not expected to have clinical sig nificance because it has been identified in 4.4% (362/8154) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs72655988). -

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

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	D
PrimateAI	Benign	0.35	T
Polyphen		0.031	.;.;B
Vest4		0.12
ClinPred		0.026	T
GERP RS		5.9
Varity_R		0.30
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs72655988; hg19: chr7-21621631; COSMIC: COSV99080603;