rs6965750

Positions:

• chr7-21784504-G-A
• chr7-21784504-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001277115.2(DNAH11):​c.9561G>A​(p.Leu3187Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,612,302 control chromosomes in the GnomAD database, including 16,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1763 hom., cov: 33)
  • Exomes 𝑓: 0.14 (14802 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.298

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 7-21784504-G-A is Benign according to our data. Variant chr7-21784504-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 178731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21784504-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.298 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.9561G>A	p.Leu3187Leu	synonymous_variant	58/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.9561G>A	p.Leu3187Leu	synonymous_variant	58/82	5	NM_001277115.2	ENSP00000475939.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22342 AN: 152066 Hom.: 1759 Cov.: 33

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0727

Gnomad AMR AF: 0.0890

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0619

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.124 AC: 30769 AN: 247318 Hom.: 2102 AF XY: 0.126 AC XY: 16894 AN XY: 134150

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0533

Gnomad ASJ exome AF: 0.141

Gnomad EAS exome AF: 0.0680

Gnomad SAS exome AF: 0.120

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.139 AC: 203401 AN: 1460118 Hom.: 14802 Cov.: 31 AF XY: 0.139 AC XY: 100991 AN XY: 726254

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0580

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.0532

Gnomad4 SAS exome AF: 0.123

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.145

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.147 AC: 22353 AN: 152184 Hom.: 1763 Cov.: 33 AF XY: 0.143 AC XY: 10657 AN XY: 74404

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.0888

Gnomad4 ASJ AF: 0.148

Gnomad4 EAS AF: 0.0621

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.124

Alfa AF: 0.134 Hom.: 3083

Bravo AF: 0.145

Asia WGS AF: 0.0970 AC: 340 AN: 3476

EpiCase AF: 0.140

EpiControl AF: 0.142

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	Leu3187Leu in exon 58 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 17.7% (695/3924) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs6965750). -
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	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	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	-0.35
CADD	Benign	5.6
DANN	Benign	0.86

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: rs6965750; hg19: chr7-21824122; COSMIC: COSV60957224;