rs17745898

Positions:

• chr7-21601000-C-G

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.3256-10C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,610,006 control chromosomes in the GnomAD database, including 17,377 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1127 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16250 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001173
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.160

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 (BayesDel_noAF=-0.83).
• BP6: Variant 7-21601000-C-G is Benign according to our data. Variant chr7-21601000-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 163101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21601000-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.3256-10C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.3256-10C>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16121 AN: 152064 Hom.: 1127 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.116 AC: 28516 AN: 244890 Hom.: 1974 AF XY: 0.122 AC XY: 16229 AN XY: 132708

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0737

Gnomad ASJ exome AF: 0.155

Gnomad EAS exome AF: 0.0324

Gnomad SAS exome AF: 0.125

Gnomad FIN exome AF: 0.0832

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.144 AC: 210202 AN: 1457822 Hom.: 16250 Cov.: 37 AF XY: 0.144 AC XY: 104662 AN XY: 725008

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.0790

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.0257

Gnomad4 SAS exome AF: 0.125

Gnomad4 FIN exome AF: 0.0874

Gnomad4 NFE exome AF: 0.159

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.106 AC: 16122 AN: 152184 Hom.: 1127 Cov.: 32 AF XY: 0.103 AC XY: 7656 AN XY: 74410

Gnomad4 AFR AF: 0.0275

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.0359

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.0853

Gnomad4 NFE AF: 0.157

Gnomad4 OTH AF: 0.129

Alfa AF: 0.129 Hom.: 277

Bravo AF: 0.105

Asia WGS AF: 0.0550 AC: 195 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	3256-10C>G in intron 16 of DNAH11: This variant is not expected to have clinical significance because it has been identified in 15.9% (1304/8180) of European Am erican chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs17745898). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.6
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.042
SpliceAI score (max)		0.080		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: rs17745898; hg19: chr7-21640618; COSMIC: COSV60953433;