rs554657293

chr7-21861917-G-Achr7-21861917-G-Cchr7-21861917-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001277115.2(DNAH11):c.11267G>A(p.Arg3756His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R3756C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.07

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-21861917-G-A is Benign according to our data. Variant chr7-21861917-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402629.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.11267G>A	p.Arg3756His	missense_variant	69/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.11267G>A	p.Arg3756His	missense_variant	69/82	5	NM_001277115.2	P1
DNAH11	ENST00000421290.1	n.450G>A		non_coding_transcript_exon_variant	4/4	4
DNAH11	ENST00000607413.5	n.530G>A		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152020 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000685 AC: 17 AN: 248060 Hom.: 0 AF XY: 0.0000520 AC XY: 7 AN XY: 134598

Gnomad AFR exome AF: 0.0000648

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000125

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.0000924 AC: 135 AN: 1461008 Hom.: 0 Cov.: 30 AF XY: 0.0000894 AC XY: 65 AN XY: 726784

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000954

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152138 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74362

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000909 AC: 11

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 2014	The p.R3763H variant (also known as c.11288G>A), located in coding exon 69 of the DNAH11 gene, results from a G to A substitution at nucleotide position 11288. The arginine at codon 3763 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6272 samples (12544 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Affects minor transcript. Not reported. Gene is associated with PCD, would not explain patient's phenotype. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.27	T
Vest4		0.32
MutPred		0.76		Gain of disorder (P = 0.1049);Gain of disorder (P = 0.1049);.;
MVP		0.73
ClinPred		0.93	D
GERP RS		5.7
Varity_R		0.25
gMVP		0.75

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: rs554657293; hg19: chr7-21901535;