rs397515541

chr5-13902053-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001369.3(DNAH5):c.1730G>C(p.Arg577Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,587,338 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: DNAH5 NM_001369.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 3.46

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 Likely_pathogenic. Variant got 7 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, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 5-13902053-C-G is Pathogenic according to our data. Variant chr5-13902053-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65637.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=2, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DNAH5	NM_001369.3	c.1730G>C	p.Arg577Thr	missense_variant, splice_region_variant	13/79	ENST00000265104.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DNAH5	ENST00000265104.5	c.1730G>C	p.Arg577Thr	missense_variant, splice_region_variant	13/79	1	NM_001369.3	P4
DNAH5	ENST00000681290.1	c.1685G>C	p.Arg562Thr	missense_variant, splice_region_variant	13/79			A1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000216 AC: 5 AN: 231028 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124632

Gnomad AFR exome AF: 0.00

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: 0.0000493

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 53 AN: 1435214 Hom.: 0 Cov.: 28 AF XY: 0.0000308 AC XY: 22 AN XY: 713648

Gnomad4 AFR exome AF: 0.00

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: 0.0000476

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74312

Gnomad4 AFR AF: 0.00

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Primary ciliary dyskinesia 3 Pathogenic:3 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: DNAH5 c.1730G>C (p.Arg577Thr) results in a non-conservative amino acid change located in the Dynein heavy chain, tail domain (IPR013594) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant leads to exon 13 skipping, resulting in premature protein truncation (example: Hofner_2006). The variant allele was found at a frequency of 2.2e-05 in 231028 control chromosomes (gnomAD). c.1730G>C has been reported in the literature in an individual affected with Primary ciliary dyskinesia (in heterozygous state), characterized by defective outer dynein arms on electron microscopy (example: Hofner_2006). The following publication has been ascertained in the context of this evaluation (PMID: 16627867). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 01, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 29, 2016	- -

Primary ciliary dyskinesia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2016	The c.1730G>C variant (also known as p.R577T), located in coding exon 13 of the DNAH5 gene, results from a G to C substitution at nucleotide position 1730. The amino acid change results in arginine to threonine at codon 577, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 13, which makes it likely to have some effect on normal mRNA splicing. This variant was detected in a patient with primary ciliary dyskinesia (characterized by defective outer dynein arms on electron microscopy). A second alteration was not detected; however, studies of the patient's respiratory epithelial cells showed exon 13 skipping, resulting in premature protein truncation (Hornef N, Am. J. Respir. Crit. Care Med. 2006 Jul; 174(2):120-6). 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 6488 samples (12976 alleles) with coverage at this position. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change affects codon 577 of the DNAH5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DNAH5 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs397515541, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of primary ciliary dyskinesia (PMID: 16627867; Invitae). 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: 65637). 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). Studies have shown that this variant results in skipping of exon 13 and introduces a premature termination codon (PMID: 16627867). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Benign	0.41	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.086	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.14
Sift	Uncertain	0.014	D
Polyphen		0.11	B
Vest4		0.60
MutPred		0.53		Loss of MoRF binding (P = 0.0176);
MVP		0.70
MPC		0.24
ClinPred		0.67	D
GERP RS		4.9
Varity_R		0.62
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.89		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.89		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: rs397515541; hg19: chr5-13902162;