rs72657379

chr7-21779056-G-Achr7-21779056-G-Cchr7-21779056-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001277115.2(DNAH11):c.9435G>A(p.Thr3145=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,613,338 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (56 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.689

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 7-21779056-G-A is Benign according to our data. Variant chr7-21779056-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226590.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr7-21779056-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.689 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00428 (652/152284) while in subpopulation NFE AF= 0.00782 (532/68022). AF 95% confidence interval is 0.00727. There are 3 homozygotes in gnomad4. There are 270 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.9435G>A	p.Thr3145=	synonymous_variant	57/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.9435G>A	p.Thr3145=	synonymous_variant	57/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00391 AC: 971 AN: 248558 Hom.: 5 AF XY: 0.00381 AC XY: 514 AN XY: 134814

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.000931

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00255

Gnomad NFE exome AF: 0.00744

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00708 AC: 10351 AN: 1461054 Hom.: 56 Cov.: 31 AF XY: 0.00692 AC XY: 5031 AN XY: 726762

Gnomad4 AFR exome AF: 0.00126

Gnomad4 AMR exome AF: 0.000940

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00251

Gnomad4 NFE exome AF: 0.00883

Gnomad4 OTH exome AF: 0.00446

GnomAD4 genome AF: 0.00428 AC: 652 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74472

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00782

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00657 Hom.: 12

Bravo AF: 0.00390

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

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

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Thr3145Thr in exon 57 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 0.7% (62/8276) of European American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs72657379). -

Primary ciliary dyskinesia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 01, 2023

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2022

DNAH11: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
Cadd	Benign	1.9
Dann	Benign	0.70

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: rs72657379; hg19: chr7-21818674;