4-64280154-GC-G

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 5.15
Variant links:
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]

Genome browser will be placed here

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
TECRLNM_001010874.5 linkuse as main transcriptc.1009del p.Ala337HisfsTer9 frameshift_variant 12/12 ENST00000381210.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TECRLENST00000381210.8 linkuse as main transcriptc.1009del p.Ala337HisfsTer9 frameshift_variant 12/121 NM_001010874.5 P1
TECRLENST00000511997.1 linkuse as main transcriptc.*24del 3_prime_UTR_variant 2/21
TECRLENST00000507440.5 linkuse as main transcriptc.964+886del intron_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000198
AC:
3
AN:
151614
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000658
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000295
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000532
AC:
77
AN:
1447378
Hom.:
0
Cov.:
30
AF XY:
0.0000528
AC XY:
38
AN XY:
719776
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000687
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.0000198
AC:
3
AN:
151614
Hom.:
0
Cov.:
32
AF XY:
0.0000270
AC XY:
2
AN XY:
73998
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000658
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000295
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189

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 submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteMar 31, 2022Based 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 submitterclinical testingAmbry GeneticsApr 13, 2023The 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1461307621; hg19: chr4-65145872; API