rs10224537

Positions:

• chr7-21600787-A-G
• chr7-21600787-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.3112A>G​(p.Thr1038Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.819 in 1,613,570 control chromosomes in the GnomAD database, including 543,034 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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. T1038V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.80 (48351 hom., cov: 30)
  • Exomes 𝑓: 0.82 (494683 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.361

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=7.558386E-7).
• BP6: Variant 7-21600787-A-G is Benign according to our data. Variant chr7-21600787-A-G is described in ClinVar as [Benign]. Clinvar id is 163100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21600787-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.3112A>G	p.Thr1038Ala	missense_variant	16/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.3112A>G	p.Thr1038Ala	missense_variant	16/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.796 AC: 120916 AN: 151858 Hom.: 48310 Cov.: 30

Gnomad AFR AF: 0.752

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.723

Gnomad ASJ AF: 0.740

Gnomad EAS AF: 0.820

Gnomad SAS AF: 0.717

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.842

Gnomad OTH AF: 0.796

GnomAD3 exomes AF: 0.782 AC: 194303 AN: 248324 Hom.: 76668 AF XY: 0.784 AC XY: 105519 AN XY: 134644

Gnomad AFR exome AF: 0.745

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.735

Gnomad EAS exome AF: 0.811

Gnomad SAS exome AF: 0.702

Gnomad FIN exome AF: 0.827

Gnomad NFE exome AF: 0.839

Gnomad OTH exome AF: 0.792

GnomAD4 exome AF: 0.821 AC: 1200035 AN: 1461594 Hom.: 494683 Cov.: 68 AF XY: 0.818 AC XY: 594577 AN XY: 727086

Gnomad4 AFR exome AF: 0.738

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.735

Gnomad4 EAS exome AF: 0.790

Gnomad4 SAS exome AF: 0.707

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.842

Gnomad4 OTH exome AF: 0.815

GnomAD4 genome AF: 0.796 AC: 121007 AN: 151976 Hom.: 48351 Cov.: 30 AF XY: 0.790 AC XY: 58717 AN XY: 74296

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.740

Gnomad4 EAS AF: 0.820

Gnomad4 SAS AF: 0.716

Gnomad4 FIN AF: 0.821

Gnomad4 NFE AF: 0.842

Gnomad4 OTH AF: 0.799

Alfa AF: 0.824 Hom.: 126620

Bravo AF: 0.788

TwinsUK AF: 0.847 AC: 3142

ALSPAC AF: 0.849 AC: 3272

ESP6500AA AF: 0.768 AC: 3046

ESP6500EA AF: 0.838 AC: 6987

ExAC AF: 0.788 AC: 95266

Asia WGS AF: 0.810 AC: 2820 AN: 3478

EpiCase AF: 0.835

EpiControl AF: 0.830

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Thr1038Ala in exon 16 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 23.2% (920/3966) of African Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs10224537). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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	Feb 01, 2024	- -

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

Dec 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.7
DANN	Benign	0.89
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.047	T;T;T
MetaRNN	Benign	7.6e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.29	T
Polyphen		0.0	.;.;B
Vest4		0.018
ClinPred		0.0011	T
GERP RS		3.6
Varity_R		0.044
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs10224537; hg19: chr7-21640405; COSMIC: COSV60940567;