19-57231759-A-ACAGCCCAG
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001015878.2(AURKC):c.94_101dupAGCCCAGC(p.Met35AlafsTer40) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,613,322 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001015878.2 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000152 AC: 23AN: 151432Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000204 AC: 51AN: 250472Hom.: 0 AF XY: 0.000185 AC XY: 25AN XY: 135450
GnomAD4 exome AF: 0.000244 AC: 357AN: 1461890Hom.: 0 Cov.: 35 AF XY: 0.000249 AC XY: 181AN XY: 727248
GnomAD4 genome AF: 0.000152 AC: 23AN: 151432Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10AN XY: 73888
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 20, 2017 | This sequence change creates a premature translational stop signal (p.Met35Alafs*40) in the AURKC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs757923465, ExAC 0.02%). This variant has not been reported in the literature in individuals with AURKC-related disease. Loss-of-function variants in AURKC are known to be pathogenic (PMID: 17435757, 19147683, 22888167). For these reasons, this variant has been classified as Pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 09, 2018 | The p.Met35AlafsX40 variant in AURKC has not been previously reported in individ uals with spermatogenic failure, but has been identified in 0.1% (11/10368) of A shkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This v ariant is predicted to cause a frameshift in some (e.g. NM_001015878.1 and NM_00 1015879.1) but not all of the transcripts produced by the gene. It occurs upstre am of the start codon of an alternate transcript (NM_003160.2) and the two known pathogenic loss of function variants in this gene (p.Tyr248X and p.Leu49TrpfsX2 3) occur downstream of the start codon in all 3 transcripts. Loss of AURKC funct ion is an established disease mechanism in individuals with spermatogenic failur e (Dieterich 2007, Ben Khelifa 2011, Ben Khelifa 2012); however, given uncertain ty around which transcripts are biologically relevant, the p.Met35AlafsX40 varia nt is uncertain. ACMG/AMP Criteria applied: None. - |
Infertility associated with multi-tailed spermatozoa and excessive DNA Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 14, 2017 | The AURKC c.94_101dupAGCCCAGC (p.Met35AlafsTer40) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for spermatogenic failure. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at