7-21901012-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001277115.2(DNAH11):c.13309C>T(p.Arg4437Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,591,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4437H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.181

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]

CDCA7L (HGNC:30777): (cell division cycle associated 7 like) Acts upstream of or within positive regulation of cell population proliferation. Located in cytosol; fibrillar center; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001277115.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.099295855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.13309C>T	p.Arg4437Cys	missense_variant	82/82	ENST00000409508.8
CDCA7L	NM_018719.5	c.*1310G>A		3_prime_UTR_variant	10/10	ENST00000406877.8
CDCA7L	NM_001127370.3	c.*1310G>A		3_prime_UTR_variant	11/11
CDCA7L	NM_001127371.3	c.*1310G>A		3_prime_UTR_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.13309C>T	p.Arg4437Cys	missense_variant	82/82	5	NM_001277115.2	P1
CDCA7L	ENST00000406877.8	c.*1310G>A		3_prime_UTR_variant	10/10	1	NM_018719.5	P1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000354 AC: 83 AN: 234432 Hom.: 0 AF XY: 0.000354 AC XY: 45 AN XY: 127238

Gnomad AFR exome AF: 0.000921

Gnomad AMR exome AF: 0.000195

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00161

Gnomad SAS exome AF: 0.000438

Gnomad FIN exome AF: 0.0000475

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000359

GnomAD4 exome AF: 0.000158 AC: 227 AN: 1439400 Hom.: 0 Cov.: 33 AF XY: 0.000160 AC XY: 114 AN XY: 713810

Gnomad4 AFR exome AF: 0.000860

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000915

Gnomad4 SAS exome AF: 0.000363

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000945

Gnomad4 OTH exome AF: 0.000320

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74456

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00174

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000205 Hom.: 1

Bravo AF: 0.000344

ESP6500AA AF: 0.000797 AC: 3

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2014	The p.R4444C variant (also known as c.13330C>T and p.R4437C), located in coding exon 82 of the DNAH11 gene, results from a C to T substitution at nucleotide position 13330. The arginine at codon 4444 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was first reported as p.R4437C and identified in two related individuals with primary ciliary diskinesia who also carried the c.9103-2A>C alteration; however, the phase (cis/trans) of the two alterations is not known (Boon M et al. Orphanet J Rare Dis. 2014;9(1):11). This variant was previously reported in the SNPDatabase as rs200466467. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.03% (4/11958) total alleles studied, having been observed in 0.08% (3/3764) African American alleles and 0.01% (1/8194) European American alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be probably damaging but tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 21, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4437 of the DNAH11 protein (p.Arg4437Cys). This variant is present in population databases (rs200466467, gnomAD 0.2%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 24450482). ClinVar contains an entry for this variant (Variation ID: 359697). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DNAH11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	11
Dann	Uncertain	0.98
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.099	T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
Vest4		0.60
MVP		0.18
ClinPred		0.18	T
GERP RS		-6.7
Varity_R		0.47
gMVP		0.58

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: rs200466467; hg19: chr7-21940630; COSMIC: COSV60974995; COSMIC: COSV60974995;