rs62447794

chr7-21635864-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):c.4501-7A>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,599,572 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (49 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002229
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.142

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 7-21635864-A-T is Benign according to our data. Variant chr7-21635864-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 220718.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Uncertain_significance=1}. Variant chr7-21635864-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00431 (656/152246) while in subpopulation NFE AF= 0.00765 (520/68018). AF 95% confidence interval is 0.0071. There are 1 homozygotes in gnomad4. There are 324 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.4501-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.4501-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	P1
DNAH11	ENST00000465593.1	n.527-7A>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00431 AC: 656 AN: 152128 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00764

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00423 AC: 973 AN: 229952 Hom.: 2 AF XY: 0.00431 AC XY: 537 AN XY: 124540

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000819

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00775

Gnomad OTH exome AF: 0.00460

GnomAD4 exome AF: 0.00759 AC: 10980 AN: 1447326 Hom.: 49 Cov.: 30 AF XY: 0.00728 AC XY: 5225 AN XY: 718196

Gnomad4 AFR exome AF: 0.00151

Gnomad4 AMR exome AF: 0.00121

Gnomad4 ASJ exome AF: 0.00244

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000584

Gnomad4 FIN exome AF: 0.00360

Gnomad4 NFE exome AF: 0.00937

Gnomad4 OTH exome AF: 0.00374

GnomAD4 genome AF: 0.00431 AC: 656 AN: 152246 Hom.: 1 Cov.: 32 AF XY: 0.00435 AC XY: 324 AN XY: 74422

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00255

Gnomad4 NFE AF: 0.00765

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00599 Hom.: 1

Bravo AF: 0.00455

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	DNAH11: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 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	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2017	c.4501-7A>T in intron 25 of DNAH11: This variant is not expected to have clinica l significance because it has been identified in 0.8% (885/116178) of European c hromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstit ute.org; dbSNP rs62447794). -

Primary ciliary dyskinesia 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	11
Dann	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00022
dbscSNV1_RF	Benign	0.044
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: rs62447794; hg19: chr7-21675482;