rs753614861

chr5-13830026-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001369.3(DNAH5):c.6249G>A(p.Met2083Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,613,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2083L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.91

Genes affected

DNAH5 (HGNC:2950): (dynein axonemal heavy chain 5) This gene encodes a dynein protein, which is part of a microtubule-associated motor protein complex consisting of heavy, light, and intermediate chains. This protein is an axonemal heavy chain dynein. It functions as a force-generating protein with ATPase activity, whereby the release of ADP is thought to produce the force-producing power stroke. Mutations in this gene cause primary ciliary dyskinesia type 3, as well as Kartagener syndrome, which are both diseases due to ciliary defects. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-13830026-C-T is Pathogenic according to our data. Variant chr5-13830026-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.6249G>A	p.Met2083Ile	missense_variant, splice_region_variant	37/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.6249G>A	p.Met2083Ile	missense_variant, splice_region_variant	37/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.6204G>A	p.Met2068Ile	missense_variant, splice_region_variant	37/79			A1
DNAH5	ENST00000683090.1	n.1180G>A		splice_region_variant, non_coding_transcript_exon_variant	2/7

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 151984 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250910 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135612

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1461236 Hom.: 0 Cov.: 33 AF XY: 0.0000647 AC XY: 47 AN XY: 726978

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000783

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 151984 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74196

Gnomad4 AFR AF: 0.0000242

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: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000291 Hom.: 0

Bravo AF: 0.0000718

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 05, 2017	The c.6249G>A pathogenic mutation (also known as p.M2083I), located in coding exon 37 of the DNAH5 gene, results from a G to A substitution at nucleotide position 6249. The methionine at codon 2083 is replaced by isoleucine, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 37, which makes it likely to have some effect on normal mRNA splicing. This variant was described in two siblings with outer dynein arm defects detected by electron microscopy, and a frameshift alteration confirmed in trans. Studies demonstrated that this alteration leads to abnormal splicing and premature protein truncation (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). In addition, this mutation was reported in two individuals with primary ciliary dyskinesia, both with situs inversus, outer dynein arm defects on electron microscopy, and a second DNAH5 alteration (Berg JS et al. Genet. Med., 2011 Mar;13:218-29; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 24, 2016	The p.Met2083Ile variant in DNAH5 has been reported in trans with a second DNAH5 variant (Met754Ilefs) in 1 individual with primary ciliary dyskinesia. Both var iants were present in 1 affected sibling (Knowles 2013). This variant has been identified in 1/66400 European chromosomes by the Exome Aggregation Consortium ( ExAC, http://exac.broadinstitute.org; dbSNP rs753614861). Please note that for diseases with clinical variability, reduced penetrance, or recessive inheritance , pathogenic variants may be present at a low frequency in the general populatio n. This variant affects the last base of the exon, which is part of the 5? splic e region, and has been shown to affect splicing (Knowles 2013). In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Met2083Ile variant is likely pathogenic in an autosomal recessive fashi on -
Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Nov 08, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 2083 of the DNAH5 protein (p.Met2083Ile). This variant also falls at the last nucleotide of exon 37, which is part of the consensus splice site for this exon. This variant is present in population databases (rs753614861, gnomAD 0.02%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 2127064, 2389146, 23261302). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 228251). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Primary ciliary dyskinesia 3 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 18, 2017	The DNAH5 c.6249G>A (p.Met2083Ile) missense variant has been identified in a compound heterozygous state in six individuals from three families with primary ciliary dyskinesia and ciliary outer dynein arm defects demonstrated via electron microscopy (Berg et al. 2011; Knowles et al. 2013; Zariwala et al. 2013). Several of these individuals were reported to exhibit situs inversus, bronchiectasis, sinusitis and otitis media. Among these individuals, a sibling pair was shown to have inherited the variant from their healthy parent. Control data are unavailable for this variant, which is reported at a frequency of 0.000196 in the African population of the Genome Aggregation Database. RT-PCR of nasal RNA from one patient who carried a frameshift variant in trans with p.Met2083Ile demonstrated that the variant affects splicing, leading to two mutant transcripts, one showing deletion of exon 37 and the other deletion of exons 36 and 37. Both transcripts led to a premature translation termination signal (Knowles et al. 2013). Based on the collective evidence, the p.Met2083Ile variant is classified as likely pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 10, 2013	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 03, 2022

Published functional studies demonstrate abnormal splicing leading to multiple aberrant transcripts (Knowles et al., 2013); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; In addition, in silico predictors suggest the missense change may have a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23261302, 21270641, 31879361, 23891469, 30067075, Poplawska_2021_Abstract) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Pathogenic	3.2	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.72		Loss of sheet (P = 0.0315);
MVP		0.75
MPC		0.12
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs753614861; hg19: chr5-13830135;