rs377388499

chr7-21894771-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001277115.2(DNAH11):c.12899G>A(p.Arg4300His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,611,818 control chromosomes in the GnomAD database, including 4 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.400

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010042906).
• BP6: Variant 7-21894771-G-A is Benign according to our data. Variant chr7-21894771-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227319.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2}. Variant chr7-21894771-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.12899G>A	p.Arg4300His	missense_variant	78/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.12899G>A	p.Arg4300His	missense_variant	78/82	5	NM_001277115.2	P1
DNAH11	ENST00000479878.1	n.192G>A		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000473 AC: 117 AN: 247394 Hom.: 2 AF XY: 0.000566 AC XY: 76 AN XY: 134240

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00218

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000303

Gnomad OTH exome AF: 0.000666

GnomAD4 exome AF: 0.000273 AC: 399 AN: 1459512 Hom.: 4 Cov.: 31 AF XY: 0.000340 AC XY: 247 AN XY: 725914

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00221

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000295 AC: 45 AN: 152306 Hom.: 0 Cov.: 33 AF XY: 0.000295 AC XY: 22 AN XY: 74474

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000321 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000536

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 27, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Primary ciliary dyskinesia 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Oct 28, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 30, 2015

p.Arg4300His in exon 78 of DNAH11: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, 5 mammals including the Egyptian jerboa, white rhinoceros, David's myoti s (bat), microbat and big brown bat have a histidine (His) at this position. In addition, it has been seen in 0.22% (34/15800) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNPrs3773 88499). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.25	T
Vest4		0.23
MVP		0.25
ClinPred		0.049	T
GERP RS		2.8
Varity_R		0.20
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs377388499; hg19: chr7-21934389;