rs117064287

chr7-21558946-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001277115.2(DNAH11):c.640A>G(p.Ile214Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00629 in 1,595,426 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0064 (54 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.94

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006872803).
• BP6: Variant 7-21558946-A-G is Benign according to our data. Variant chr7-21558946-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166998.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00563 (857/152324) while in subpopulation NFE AF= 0.0092 (626/68014). AF 95% confidence interval is 0.00861. There are 5 homozygotes in gnomad4. There are 430 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.640A>G	p.Ile214Val	missense_variant	3/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.640A>G	p.Ile214Val	missense_variant	3/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 856 AN: 152206 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0114

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00546 AC: 1199 AN: 219534 Hom.: 8 AF XY: 0.00532 AC XY: 627 AN XY: 117788

Gnomad AFR exome AF: 0.00113

Gnomad AMR exome AF: 0.000832

Gnomad ASJ exome AF: 0.00436

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000598

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.00832

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00636 AC: 9180 AN: 1443102 Hom.: 54 Cov.: 31 AF XY: 0.00633 AC XY: 4531 AN XY: 715680

Gnomad4 AFR exome AF: 0.000753

Gnomad4 AMR exome AF: 0.00100

Gnomad4 ASJ exome AF: 0.00405

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000398

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00723

Gnomad4 OTH exome AF: 0.00474

GnomAD4 genome AF: 0.00563 AC: 857 AN: 152324 Hom.: 5 Cov.: 33 AF XY: 0.00577 AC XY: 430 AN XY: 74500

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0114

Gnomad4 NFE AF: 0.00920

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00756 Hom.: 14

Bravo AF: 0.00411

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00675 AC: 26

ESP6500AA AF: 0.00241 AC: 9

ESP6500EA AF: 0.00732 AC: 60

ExAC AF: 0.00497 AC: 599

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 26, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	DNAH11: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2022	- -

Primary ciliary dyskinesia 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Dec 19, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.067
Eigen_PC	Benign	0.14
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T;T;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.89	D
PrimateAI	Benign	0.36	T
Polyphen		0.0010	.;.;B
Vest4		0.27
MVP		0.16
ClinPred		0.029	T
GERP RS		6.0
Varity_R		0.033
gMVP		0.10

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: rs117064287; hg19: chr7-21598564;