chr5-13902053-C-G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
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 Likely pathogenic (★★).
Frequency
Consequence
NM_001369.3 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.1730G>C | p.Arg577Thr | missense_variant, splice_region_variant | Exon 13 of 79 | 1 | NM_001369.3 | ENSP00000265104.4 | ||
DNAH5 | ENST00000681290.1 | c.1685G>C | p.Arg562Thr | missense_variant, splice_region_variant | Exon 13 of 79 | ENSP00000505288.1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000216 AC: 5AN: 231028Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 124632
GnomAD4 exome AF: 0.0000369 AC: 53AN: 1435214Hom.: 0 Cov.: 28 AF XY: 0.0000308 AC XY: 22AN XY: 713648
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152124Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74312
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:3Other:1
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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. -
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Primary ciliary dyskinesia Pathogenic:2
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. -
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 altered 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; internal data). 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 produces a non-functional protein and/or introduces a premature termination codon (PMID: 16627867). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
Functional studies and in silico splice predictors suggest that this variant causes skipping of exon 13 (PMID: 16627867); This variant is associated with the following publications: (PMID: 34758253, 16627867, 31879361) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at