rs2285944

chr7-21543346-A-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.101A>T(p.Glu34Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.481 in 1,550,724 control chromosomes in the GnomAD database, including 181,836 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E34L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.45 (15491 hom., cov: 34)
  • Exomes 𝑓: 0.48 (166345 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.369

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=3.2663345E-4).
• BP6: Variant 7-21543346-A-T is Benign according to our data. Variant chr7-21543346-A-T is described in ClinVar as [Benign]. Clinvar id is 93683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21543346-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.101A>T	p.Glu34Val	missense_variant	1/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.101A>T	p.Glu34Val	missense_variant	1/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67793 AN: 151720 Hom.: 15472 Cov.: 34

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.323

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.494

Gnomad OTH AF: 0.465

GnomAD3 exomes AF: 0.437 AC: 66886 AN: 152884 Hom.: 15340 AF XY: 0.449 AC XY: 36502 AN XY: 81260

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.307

Gnomad ASJ exome AF: 0.494

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.508

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.494

Gnomad OTH exome AF: 0.448

GnomAD4 exome AF: 0.485 AC: 678031 AN: 1398886 Hom.: 166345 Cov.: 74 AF XY: 0.486 AC XY: 335054 AN XY: 689954

Gnomad4 AFR exome AF: 0.429

Gnomad4 AMR exome AF: 0.326

Gnomad4 ASJ exome AF: 0.493

Gnomad4 EAS exome AF: 0.300

Gnomad4 SAS exome AF: 0.509

Gnomad4 FIN exome AF: 0.430

Gnomad4 NFE exome AF: 0.499

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.447 AC: 67846 AN: 151838 Hom.: 15491 Cov.: 34 AF XY: 0.442 AC XY: 32813 AN XY: 74214

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.363

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.261

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.494

Gnomad4 OTH AF: 0.461

Alfa AF: 0.482 Hom.: 5716

Bravo AF: 0.441

TwinsUK AF: 0.495 AC: 1835

ALSPAC AF: 0.491 AC: 1892

ESP6500AA AF: 0.380 AC: 1320

ESP6500EA AF: 0.451 AC: 3331

ExAC AF: 0.325 AC: 18950

Asia WGS AF: 0.334 AC: 1161 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Glu34Val in exon 1 of DNAH11: This variant is not expected to have clinical sign ificance because it has been identified in 45.1% (3331/7390) of European America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs2285944). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 28, 2013	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -

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
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.00033	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.58	T
Polyphen		0.86	.;.;P
Vest4		0.12
ClinPred		0.0083	T
GERP RS		2.3
Varity_R		0.39
gMVP		0.57

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: rs2285944; hg19: chr7-21582964; COSMIC: COSV60985216; COSMIC: COSV60985216;