rs727505321

chr7-21704597-G-Achr7-21704597-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001277115.2(DNAH11):c.6437G>A(p.Arg2146His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,608,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2146C) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.448

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.092820585).
• BP6: Variant 7-21704597-G-A is Benign according to our data. Variant chr7-21704597-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 180063.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.6437G>A	p.Arg2146His	missense_variant	38/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.6437G>A	p.Arg2146His	missense_variant	38/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000704 AC: 17 AN: 241460 Hom.: 0 AF XY: 0.0000535 AC XY: 7 AN XY: 130902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000620

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.0000350

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000109

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000112 AC: 163 AN: 1456376 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77 AN XY: 724170

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.0000693

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000131

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000115 Hom.: 0

Bravo AF: 0.0000491

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000744 AC: 9

EpiCase AF: 0.000219

EpiControl AF: 0.0000596

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 05, 2014	p.Arg2146His in exon 38 of DNAH11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, >10 mammals carry a histidine (His) at this position despite high nearby amino acid conservation. -

Primary ciliary dyskinesia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 11, 2024	The c.6437G>A (p.R2146H) alteration is located in exon 38 (coding exon 38) of the DNAH11 gene. This alteration results from a G to A substitution at nucleotide position 6437, causing the arginine (R) at amino acid position 2146 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	9.3
Dann	Benign	0.97
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.093	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.19	T
Vest4		0.31
MVP		0.23
ClinPred		0.064	T
GERP RS		-2.0
Varity_R		0.074
gMVP		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: rs727505321; hg19: chr7-21744215; COSMIC: COSV60969693; COSMIC: COSV60969693;