7-21543440-C-T

Position:

• chr7-21543440-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 2P and 17B. PM2 BP4_Strong BP6_Very_Strong BP7 BS1

The NM_001277115.2(DNAH11):​c.195C>T​(p.Arg65Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,561,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00099 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: DNAH11 NM_001277115.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.150

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]

DNAH11 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 7-21543440-C-T is Benign according to our data. Variant chr7-21543440-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 525553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000991 (151/152328) while in subpopulation AFR AF= 0.00334 (139/41588). AF 95% confidence interval is 0.00289. There are 0 homozygotes in gnomad4. There are 74 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DNAH11	NM_001277115.2	c.195C>T	p.Arg65Arg	synonymous_variant	1/82	ENST00000409508.8	NP_001264044.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DNAH11	ENST00000409508.8	c.195C>T	p.Arg65Arg	synonymous_variant	1/82	5	NM_001277115.2	ENSP00000475939.1
DNAH11	ENST00000607050.1	n.-6C>T		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00340

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000271 AC: 46 AN: 169774 Hom.: 1 AF XY: 0.000221 AC XY: 20 AN XY: 90652

Gnomad AFR exome AF: 0.00400

Gnomad AMR exome AF: 0.000272

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000421

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000108 AC: 152 AN: 1409666 Hom.: 1 Cov.: 35 AF XY: 0.0000862 AC XY: 60 AN XY: 696286

Gnomad4 AFR exome AF: 0.00371

Gnomad4 AMR exome AF: 0.000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000749

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000184

Gnomad4 OTH exome AF: 0.000257

GnomAD4 genome AF: 0.000991 AC: 151 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.000994 AC XY: 74 AN XY: 74476

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000376 Hom.: 0

Bravo AF: 0.00115

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 11, 2016	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

DNAH11-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	11
DANN	Benign	0.97

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: rs369285943; hg19: chr7-21583058;