4-64280154-GC-G
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_001010874.5(TECRL):c.1009del(p.Ala337HisfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.00005 in 1,598,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )
Consequence
TECRL
NM_001010874.5 frameshift
NM_001010874.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.15
Genes affected
TECRL (HGNC:27365): (trans-2,3-enoyl-CoA reductase like) The protein encoded by this gene contains a ubiquitin-like domain in the N-terminal region, three transmembrane segments and a C-terminal 3-oxo-5-alpha steroid 4-dehydrogenase domain. The protein belongs to the steroid 5-alpha reductase family. Mutations in this gene result in ventricular tachycardia, catecholaminergic polymorphic, 3. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.076 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-64280154-GC-G is Pathogenic according to our data. Variant chr4-64280154-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1794643.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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TECRL | NM_001010874.5 | c.1009del | p.Ala337HisfsTer9 | frameshift_variant | 12/12 | ENST00000381210.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TECRL | ENST00000381210.8 | c.1009del | p.Ala337HisfsTer9 | frameshift_variant | 12/12 | 1 | NM_001010874.5 | P1 | |
TECRL | ENST00000511997.1 | c.*24del | 3_prime_UTR_variant | 2/2 | 1 | ||||
TECRL | ENST00000507440.5 | c.964+886del | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000198 AC: 3AN: 151614Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000532 AC: 77AN: 1447378Hom.: 0 Cov.: 30 AF XY: 0.0000528 AC XY: 38AN XY: 719776
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GnomAD4 genome AF: 0.0000198 AC: 3AN: 151614Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 73998
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with catecholaminergic polymorphic ventricular tachycardia 3 (MIM#614021). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. This gene has been described to be associated with overlapping clinical features of both long QT syndrome and CPVT (PMID: 27861123). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 3 heterozygotes, 0 homozygotes). (SP) 0600 - Variant affects the annotated 3-oxo-5-alpha-steroid 4-dehydrogenase domain (DECIPHER). (I) 0705 - No comparable downstream truncating variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1202 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (NM_001010874.4:c.587G>A;p.(Arg196Gln)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2023 | The c.1009delG variant, located in coding exon 12 of the TECRL gene, results from a deletion of one nucleotide at nucleotide position 1009, causing a translational frameshift with a predicted alternate stop codon (p.A337Hfs*9). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, this region of the TECRL gene is excluded from other biologically relevant TECRL transcripts. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at