7-21861948-T-C

Position:

• chr7-21861948-T-C

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.11298T>C​(p.His3766=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.779 in 1,613,306 control chromosomes in the GnomAD database, including 496,202 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (40341 hom., cov: 30)
  • Exomes 𝑓: 0.79 (455861 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.36

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=-0.8).
• BP6: Variant 7-21861948-T-C is Benign according to our data. Variant chr7-21861948-T-C is described in ClinVar as [Benign]. Clinvar id is 163126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21861948-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.11298T>C	p.His3766=	synonymous_variant	69/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.11298T>C	p.His3766=	synonymous_variant	69/82	5	NM_001277115.2	ENSP00000475939	P1
DNAH11	ENST00000421290.1	n.481T>C		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5	n.561T>C		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109280 AN: 151842 Hom.: 40296 Cov.: 30

Gnomad AFR AF: 0.590

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.827

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.771

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.814

Gnomad OTH AF: 0.744

GnomAD3 exomes AF: 0.721 AC: 179230 AN: 248552 Hom.: 66221 AF XY: 0.731 AC XY: 98529 AN XY: 134840

Gnomad AFR exome AF: 0.586

Gnomad AMR exome AF: 0.569

Gnomad ASJ exome AF: 0.816

Gnomad EAS exome AF: 0.541

Gnomad SAS exome AF: 0.669

Gnomad FIN exome AF: 0.760

Gnomad NFE exome AF: 0.811

Gnomad OTH exome AF: 0.752

GnomAD4 exome AF: 0.786 AC: 1148072 AN: 1461346 Hom.: 455861 Cov.: 52 AF XY: 0.784 AC XY: 569803 AN XY: 726950

Gnomad4 AFR exome AF: 0.587

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.813

Gnomad4 EAS exome AF: 0.536

Gnomad4 SAS exome AF: 0.674

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.819

Gnomad4 OTH exome AF: 0.770

GnomAD4 genome AF: 0.720 AC: 109375 AN: 151960 Hom.: 40341 Cov.: 30 AF XY: 0.716 AC XY: 53141 AN XY: 74268

Gnomad4 AFR AF: 0.591

Gnomad4 AMR AF: 0.654

Gnomad4 ASJ AF: 0.827

Gnomad4 EAS AF: 0.542

Gnomad4 SAS AF: 0.662

Gnomad4 FIN AF: 0.771

Gnomad4 NFE AF: 0.814

Gnomad4 OTH AF: 0.745

Alfa AF: 0.792 Hom.: 102107

Bravo AF: 0.705

Asia WGS AF: 0.615 AC: 2140 AN: 3478

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	His3766His in exon 69 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 38.0% (1553/4084) of African American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs4722067). -
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, 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	Labcorp Genetics (formerly Invitae), Labcorp	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	-0.80
CADD	Benign	0.0070
DANN	Benign	0.29

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: rs4722067; hg19: chr7-21901566; COSMIC: COSV60954482;