chr5-13916424-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_001369.3(DNAH5):c.1121T>C(p.Ile374Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,558,784 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. I374I) 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_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAH5 | NM_001369.3 | c.1121T>C | p.Ile374Thr | missense_variant | 9/79 | ENST00000265104.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAH5 | ENST00000265104.5 | c.1121T>C | p.Ile374Thr | missense_variant | 9/79 | 1 | NM_001369.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000585 AC: 89AN: 152012Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000751 AC: 188AN: 250334Hom.: 0 AF XY: 0.000820 AC XY: 111AN XY: 135378
GnomAD4 exome AF: 0.00131 AC: 1839AN: 1406654Hom.: 4 Cov.: 24 AF XY: 0.00123 AC XY: 867AN XY: 702782
GnomAD4 genome ? AF: 0.000585 AC: 89AN: 152130Hom.: 1 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74380
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 3 Pathogenic:1Uncertain:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 10, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 22, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jul 15, 2021 | - - |
Primary ciliary dyskinesia Uncertain:3Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2019 | The p.I374T variant (also known as c.1121T>C), located in coding exon 9 of the DNAH5 gene, results from a T to C substitution at nucleotide position 1121. The isoleucine at codon 374 is replaced by threonine, an amino acid with similar properties. This variant was identified in a child with primary ciliary dyskinesia and situs inversus in conjunction with another DNAH5 variant in trans (Knowles MR et al. Am. J. Hum. Genet., 2013 Jan;92:99-106). Based on data from gnomAD, the C allele has an overall frequency of approximately 0.071% (201/281530) total alleles studied. The highest observed frequency was 0.162% (82/50458) of Northwestern European alleles. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Apr 18, 2019 | - - |
not provided Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 29, 2017 | The I374T variant in the DNAH5 gene has been reported previously in trans with another DNAH5 variant in an individual with primary ciliary dyskinesia (Knowles et al., 2013). The I374T variant is observed in 63/65,796 (0.096%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The I374T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret I374T as a variant of uncertain significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at