rs769544175
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate
The NM_001369.3(DNAH5):c.6444G>A(p.Gln2148=) variant causes a splice region, synonymous change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Consequence
NM_001369.3 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.6444G>A | p.Gln2148= | splice_region_variant, synonymous_variant | 38/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.6444G>A | p.Gln2148= | splice_region_variant, synonymous_variant | 38/79 | 1 | NM_001369.3 | P4 | |
DNAH5 | ENST00000681290.1 | c.6399G>A | p.Gln2133= | splice_region_variant, synonymous_variant | 38/79 | A1 | |||
DNAH5 | ENST00000683090.1 | n.1375G>A | splice_region_variant, non_coding_transcript_exon_variant | 3/7 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251320Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135826
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461812Hom.: 0 Cov.: 37 AF XY: 0.00000688 AC XY: 5AN XY: 727206
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152154Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74324
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 09, 2024 | This sequence change affects codon 2148 of the DNAH5 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the DNAH5 protein. This variant also falls at the last nucleotide of exon 38, which is part of the consensus splice site for this exon. This variant is present in population databases (rs769544175, gnomAD 0.004%). This variant has been observed in individual(s) with clinical features of primary ciliary dyskinesia (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: 576446). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at