4-64280122-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001010874.5(TECRL):ā€‹c.1042T>Cā€‹(p.Phe348Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

TECRL
NM_001010874.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.06
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 Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TECRLNM_001010874.5 linkuse as main transcriptc.1042T>C p.Phe348Leu missense_variant 12/12 ENST00000381210.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TECRLENST00000381210.8 linkuse as main transcriptc.1042T>C p.Phe348Leu missense_variant 12/121 NM_001010874.5 P1
TECRLENST00000511997.1 linkuse as main transcriptc.*57T>C 3_prime_UTR_variant 2/21
TECRLENST00000507440.5 linkuse as main transcriptc.964+919T>C intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1451986
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
722144
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:
0.0000119
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 06, 2024The p.F348L variant (also known as c.1042T>C), located in coding exon 12 of the TECRL gene, results from a T to C substitution at nucleotide position 1042. The phenylalanine at codon 348 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.87
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.80
D
Eigen
Uncertain
0.53
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.61
T
M_CAP
Benign
0.071
D
MetaRNN
Pathogenic
0.96
D
MetaSVM
Benign
-0.49
T
MutationAssessor
Pathogenic
3.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-5.3
D
REVEL
Uncertain
0.43
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0050
D
Polyphen
0.89
P
Vest4
0.59
MutPred
0.86
Gain of catalytic residue at F348 (P = 0.0608);
MVP
0.51
MPC
0.036
ClinPred
0.99
D
GERP RS
5.1
Varity_R
0.78
gMVP
0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-65145840; API