rs62445328

Positions:

• chr7-21745031-C-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.8478C>T​(p.His2826=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 1,609,286 control chromosomes in the GnomAD database, including 47 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 0.0039 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (45 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.182

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=-0.42).
• BP6: Variant 7-21745031-C-T is Benign according to our data. Variant chr7-21745031-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220474.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr7-21745031-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.182 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00391 (596/152280) while in subpopulation NFE AF= 0.00687 (467/68010). AF 95% confidence interval is 0.00635. There are 2 homozygotes in gnomad4. There are 298 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.8478C>T	p.His2826=	synonymous_variant	51/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.8478C>T	p.His2826=	synonymous_variant	51/82	5	NM_001277115.2	ENSP00000475939	P1

Frequencies

GnomAD3 genomes AF: 0.00392 AC: 596 AN: 152162 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00687

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00369 AC: 889 AN: 240852 Hom.: 6 AF XY: 0.00374 AC XY: 487 AN XY: 130214

Gnomad AFR exome AF: 0.00108

Gnomad AMR exome AF: 0.000417

Gnomad ASJ exome AF: 0.00234

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000241

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.00707

Gnomad OTH exome AF: 0.00254

GnomAD4 exome AF: 0.00675 AC: 9828 AN: 1457006 Hom.: 45 Cov.: 31 AF XY: 0.00648 AC XY: 4689 AN XY: 724092

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.000499

Gnomad4 ASJ exome AF: 0.00254

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000176

Gnomad4 FIN exome AF: 0.00288

Gnomad4 NFE exome AF: 0.00837

Gnomad4 OTH exome AF: 0.00388

GnomAD4 genome AF: 0.00391 AC: 596 AN: 152280 Hom.: 2 Cov.: 33 AF XY: 0.00400 AC XY: 298 AN XY: 74452

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00687

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00686 Hom.: 5

Bravo AF: 0.00420

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2024

DNAH11: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	2.3
DANN	Benign	0.31

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: rs62445328; hg19: chr7-21784649;