rs749862482
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001369.3(DNAH5):āc.13745A>Gā(p.Tyr4582Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. Y4582Y) has been classified as Likely benign.
Frequency
Consequence
NM_001369.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.13745A>G | p.Tyr4582Cys | missense_variant | 79/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.13745A>G | p.Tyr4582Cys | missense_variant | 79/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.13700A>G | p.Tyr4567Cys | missense_variant | 79/79 | A1 | |||
DNAH5 | ENST00000683611.1 | n.1078A>G | non_coding_transcript_exon_variant | 5/5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 151850Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250366Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135362
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461782Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8AN XY: 727188
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 151850Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2AN XY: 74138
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces tyrosine with cysteine at codon 4582 of the DNAH5 protein (p.Tyr4582Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs749862482, ExAC 0.002%). This variant has not been reported in the literature in individuals affected with DNAH5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 05, 2023 | The p.Y4582C variant (also known as c.13745A>G), located in coding exon 79 of the DNAH5 gene, results from an A to G substitution at nucleotide position 13745. The tyrosine at codon 4582 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly 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. - |
Primary ciliary dyskinesia 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at