rs140048925

chr7-21704576-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001277115.2(DNAH11):c.6416G>A(p.Arg2139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000925 in 1,613,728 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00056 (5 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.34

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 (MetaRNN=0.006824881).
• BP6: Variant 7-21704576-G-A is Benign according to our data. Variant chr7-21704576-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 238929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-21704576-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00443 (674/152294) while in subpopulation AFR AF= 0.0144 (598/41552). AF 95% confidence interval is 0.0134. There are 4 homozygotes in gnomad4. There are 325 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.6416G>A	p.Arg2139Lys	missense_variant	38/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.6416G>A	p.Arg2139Lys	missense_variant	38/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152176 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00115 AC: 285 AN: 248616 Hom.: 1 AF XY: 0.000853 AC XY: 115 AN XY: 134886

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000983

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000799

Gnomad OTH exome AF: 0.000995

GnomAD4 exome AF: 0.000560 AC: 819 AN: 1461434 Hom.: 5 Cov.: 32 AF XY: 0.000469 AC XY: 341 AN XY: 726986

Gnomad4 AFR exome AF: 0.0165

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000104

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152294 Hom.: 4 Cov.: 32 AF XY: 0.00436 AC XY: 325 AN XY: 74474

Gnomad4 AFR AF: 0.0144

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00214 Hom.: 1

Bravo AF: 0.00516

ESP6500AA AF: 0.0115 AC: 46

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.00139 AC: 168

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Arg2139Lys in exon 38 of DNAH11: This variant is not expected to have clinical s ignificance because it has been identified in 1.1% (46/4016) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs140048925). -

Primary ciliary dyskinesia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Apr 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	17
Dann	Benign	0.83
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.62	T;T;T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.32	T
Vest4		0.34
MVP		0.27
ClinPred		0.0023	T
GERP RS		3.2
Varity_R		0.064
gMVP		0.38

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: rs140048925; hg19: chr7-21744194;