rs2072221

chr7-21735825-G-Achr7-21735825-G-Cchr7-21735825-G-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.7626G>A(p.Thr2542=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.855 in 1,610,410 control chromosomes in the GnomAD database, including 592,010 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. T2542T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.83 (53172 hom., cov: 32)
  • Exomes 𝑓: 0.86 (538838 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.496

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=-0.67).
• BP6: Variant 7-21735825-G-A is Benign according to our data. Variant chr7-21735825-G-A is described in ClinVar as [Benign]. Clinvar id is 163110.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21735825-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.496 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.7626G>A	p.Thr2542=	synonymous_variant	46/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.7626G>A	p.Thr2542=	synonymous_variant	46/82	5	NM_001277115.2	P1
DNAH11	ENST00000605912.1	c.186G>A	p.Thr62=	synonymous_variant	1/4	3

Frequencies

GnomAD3 genomes AF: 0.833 AC: 126621 AN: 152026 Hom.: 53154 Cov.: 32

Gnomad AFR AF: 0.795

Gnomad AMI AF: 0.863

Gnomad AMR AF: 0.868

Gnomad ASJ AF: 0.769

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.904

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.817

GnomAD3 exomes AF: 0.825 AC: 204412 AN: 247696 Hom.: 85552 AF XY: 0.827 AC XY: 111030 AN XY: 134334

Gnomad AFR exome AF: 0.796

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.777

Gnomad EAS exome AF: 0.519

Gnomad SAS exome AF: 0.785

Gnomad FIN exome AF: 0.900

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.828

GnomAD4 exome AF: 0.857 AC: 1250264 AN: 1458266 Hom.: 538838 Cov.: 47 AF XY: 0.856 AC XY: 620240 AN XY: 724930

Gnomad4 AFR exome AF: 0.794

Gnomad4 AMR exome AF: 0.867

Gnomad4 ASJ exome AF: 0.775

Gnomad4 EAS exome AF: 0.566

Gnomad4 SAS exome AF: 0.790

Gnomad4 FIN exome AF: 0.897

Gnomad4 NFE exome AF: 0.877

Gnomad4 OTH exome AF: 0.828

GnomAD4 genome AF: 0.833 AC: 126695 AN: 152144 Hom.: 53172 Cov.: 32 AF XY: 0.832 AC XY: 61855 AN XY: 74360

Gnomad4 AFR AF: 0.795

Gnomad4 AMR AF: 0.868

Gnomad4 ASJ AF: 0.769

Gnomad4 EAS AF: 0.527

Gnomad4 SAS AF: 0.760

Gnomad4 FIN AF: 0.904

Gnomad4 NFE AF: 0.869

Gnomad4 OTH AF: 0.815

Alfa AF: 0.856 Hom.: 97723

Bravo AF: 0.839

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Thr2542Thr in exon 46 of DNAH11: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 15.2% (589/3870) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2072221). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	0.13
Dann	Benign	0.43

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: rs2072221; hg19: chr7-21775443; COSMIC: COSV60961001;