7-21735769-T-C

Position:

• chr7-21735769-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001277115.2(DNAH11):​c.7570T>C​(p.Leu2524Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,770 control chromosomes in the GnomAD database, including 6,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1799 hom., cov: 33)
  • Exomes 𝑓: 0.055 (4820 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.995

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 7-21735769-T-C is Benign according to our data. Variant chr7-21735769-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 163109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21735769-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.995 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.7570T>C	p.Leu2524Leu	synonymous_variant	46/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.7570T>C	p.Leu2524Leu	synonymous_variant	46/82	5	NM_001277115.2	ENSP00000475939.1
DNAH11	ENST00000605912.1	c.130T>C	p.Leu44Leu	synonymous_variant	1/4	3		ENSP00000476068.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17668 AN: 152052 Hom.: 1791 Cov.: 33

Gnomad AFR AF: 0.247

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.181

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0353

Gnomad OTH AF: 0.108

GnomAD3 exomes AF: 0.0973 AC: 24236 AN: 249190 Hom.: 2330 AF XY: 0.0869 AC XY: 11742 AN XY: 135182

Gnomad AFR exome AF: 0.250

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.0651

Gnomad EAS exome AF: 0.208

Gnomad SAS exome AF: 0.0629

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0355

Gnomad OTH exome AF: 0.0802

GnomAD4 exome AF: 0.0548 AC: 80113 AN: 1461600 Hom.: 4820 Cov.: 33 AF XY: 0.0536 AC XY: 39000 AN XY: 727082

Gnomad4 AFR exome AF: 0.249

Gnomad4 AMR exome AF: 0.242

Gnomad4 ASJ exome AF: 0.0676

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.0576

Gnomad4 FIN exome AF: 0.0390

Gnomad4 NFE exome AF: 0.0345

Gnomad4 OTH exome AF: 0.0692

GnomAD4 genome AF: 0.116 AC: 17707 AN: 152170 Hom.: 1799 Cov.: 33 AF XY: 0.117 AC XY: 8706 AN XY: 74394

Gnomad4 AFR AF: 0.247

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.0651

Gnomad4 FIN AF: 0.0402

Gnomad4 NFE AF: 0.0352

Gnomad4 OTH AF: 0.106

Alfa AF: 0.0543 Hom.: 1051

Bravo AF: 0.136

EpiCase AF: 0.0374

EpiControl AF: 0.0407

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	Leu2524Leu in exon 46 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 22.3% (860/3850) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2072220). -

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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.7
DANN	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs2072220; hg19: chr7-21775387; COSMIC: COSV60946294;