rs72658822

Positions:

• chr7-21892413-T-C

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.12508-12T>C 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 0.0183 in 1,596,596 control chromosomes in the GnomAD database, including 457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (115 hom., cov: 32)
  • Exomes 𝑓: 0.017 (342 hom.)
• Consequence: DNAH11 NM_001277115.2 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002397
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.300

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=-0.73).
• BP6: Variant 7-21892413-T-C is Benign according to our data. Variant chr7-21892413-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 178736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21892413-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.12508-12T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.12508-12T>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001277115.2	ENSP00000475939	P1

Frequencies

GnomAD3 genomes AF: 0.0308 AC: 4687 AN: 152112 Hom.: 114 Cov.: 32

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.0222

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0310

GnomAD3 exomes AF: 0.0217 AC: 5235 AN: 241500 Hom.: 89 AF XY: 0.0219 AC XY: 2871 AN XY: 131034

Gnomad AFR exome AF: 0.0648

Gnomad AMR exome AF: 0.0164

Gnomad ASJ exome AF: 0.0304

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.0341

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0155

Gnomad OTH exome AF: 0.0257

GnomAD4 exome AF: 0.0170 AC: 24495 AN: 1444366 Hom.: 342 Cov.: 30 AF XY: 0.0176 AC XY: 12625 AN XY: 715580

Gnomad4 AFR exome AF: 0.0656

Gnomad4 AMR exome AF: 0.0165

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.0151

Gnomad4 SAS exome AF: 0.0340

Gnomad4 FIN exome AF: 0.0115

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0225

GnomAD4 genome AF: 0.0309 AC: 4697 AN: 152230 Hom.: 115 Cov.: 32 AF XY: 0.0310 AC XY: 2310 AN XY: 74420

Gnomad4 AFR AF: 0.0645

Gnomad4 AMR AF: 0.0268

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.0218

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.0124

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0321

Alfa AF: 0.0243 Hom.: 14

Bravo AF: 0.0333

Asia WGS AF: 0.0350 AC: 121 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	12508-12T>C in intron 76 of DNAH11: This variant is not expected to have clinica l significance because it has been identified in 5.7% (220/3868) of African Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs72658822). -

Primary ciliary dyskinesia Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 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	Feb 24, 2019	- -
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	-0.73
CADD	Benign	13
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.11		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: rs72658822; hg19: chr7-21932031;