rs4615458

Positions:

• chr7-21591364-A-G
• chr7-21591364-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001277115.2(DNAH11):​c.2454A>G​(p.Ala818=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 1,613,416 control chromosomes in the GnomAD database, including 148,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A818A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (16236 hom., cov: 31)
  • Exomes 𝑓: 0.42 (131804 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.914

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-21591364-A-G is Benign according to our data. Variant chr7-21591364-A-G is described in ClinVar as [Benign]. Clinvar id is 93684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21591364-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.914 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.2454A>G	p.Ala818=	synonymous_variant	14/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.2454A>G	p.Ala818=	synonymous_variant	14/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.451 AC: 68478 AN: 151740 Hom.: 16205 Cov.: 31

Gnomad AFR AF: 0.552

Gnomad AMI AF: 0.160

Gnomad AMR AF: 0.386

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.442

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.439

GnomAD3 exomes AF: 0.428 AC: 106424 AN: 248642 Hom.: 24398 AF XY: 0.428 AC XY: 57684 AN XY: 134892

Gnomad AFR exome AF: 0.548

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.354

Gnomad EAS exome AF: 0.782

Gnomad SAS exome AF: 0.424

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.395

GnomAD4 exome AF: 0.419 AC: 611928 AN: 1461558 Hom.: 131804 Cov.: 59 AF XY: 0.417 AC XY: 303393 AN XY: 727058

Gnomad4 AFR exome AF: 0.547

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.353

Gnomad4 EAS exome AF: 0.753

Gnomad4 SAS exome AF: 0.424

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.408

Gnomad4 OTH exome AF: 0.434

GnomAD4 genome AF: 0.451 AC: 68551 AN: 151858 Hom.: 16236 Cov.: 31 AF XY: 0.451 AC XY: 33499 AN XY: 74226

Gnomad4 AFR AF: 0.552

Gnomad4 AMR AF: 0.385

Gnomad4 ASJ AF: 0.342

Gnomad4 EAS AF: 0.780

Gnomad4 SAS AF: 0.442

Gnomad4 FIN AF: 0.392

Gnomad4 NFE AF: 0.400

Gnomad4 OTH AF: 0.440

Alfa AF: 0.420 Hom.: 7571

Bravo AF: 0.456

Asia WGS AF: 0.605 AC: 2104 AN: 3478

EpiCase AF: 0.396

EpiControl AF: 0.398

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Ala818Ala in exon 14 of DNAH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 48.2% (2040/4230) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4615458). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Primary ciliary dyskinesia Benign:2

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

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.53
DANN	Benign	0.40

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: rs4615458; hg19: chr7-21630982; COSMIC: COSV60940541;