rs202034810

Positions:

• chr7-21658841-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4 BP6

The NM_001277115.2(DNAH11):​c.5138C>T​(p.Thr1713Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000693 in 1,601,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1713T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: DNAH11 NM_001277115.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.60

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35670462).
• BP6: Variant 7-21658841-C-T is Benign according to our data. Variant chr7-21658841-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525267.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH11	NM_001277115.2	c.5138C>T	p.Thr1713Met	missense_variant	30/82	ENST00000409508.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH11	ENST00000409508.8	c.5138C>T	p.Thr1713Met	missense_variant	30/82	5	NM_001277115.2	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151998 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000868 AC: 20 AN: 230482 Hom.: 0 AF XY: 0.0000563 AC XY: 7 AN XY: 124386

Gnomad AFR exome AF: 0.00106

Gnomad AMR exome AF: 0.0000619

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000599

Gnomad SAS exome AF: 0.0000358

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000966

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000393 AC: 57 AN: 1449826 Hom.: 0 Cov.: 31 AF XY: 0.0000375 AC XY: 27 AN XY: 719868

Gnomad4 AFR exome AF: 0.00120

Gnomad4 AMR exome AF: 0.0000467

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000633

Gnomad4 OTH exome AF: 0.0000501

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.000377 AC XY: 28 AN XY: 74356

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000672 Hom.: 0

Bravo AF: 0.000438

ESP6500AA AF: 0.000795 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

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	Aug 17, 2018	The p.T1713M variant (also known as c.5138C>T), located in coding exon 30 of the DNAH11 gene, results from a C to T substitution at nucleotide position 5138. The threonine at codon 1713 is replaced by methionine, an amino acid with similar properties. 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 alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

DNAH11-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	0.67	D
PrimateAI	Benign	0.42	T
Vest4		0.69
MVP		0.63
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.31
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs202034810; hg19: chr7-21698459; COSMIC: COSV60969453;