ENST00000511997.1:c.83G>T

Variant names:

• chr4-64280180-C-A
• rs563042010
• ENST00000511997.1:c.83G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM4 BP6

The ENST00000511997.1(TECRL):​c.83G>T​(p.Ter28Leuext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000195 in 1,536,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TECRL ENST00000511997.1 stop_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.28
• Publications: 0 publications found

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]

TECRL Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in ENST00000511997.1 Downstream stopcodon found after 27 codons.
• BP6: Variant 4-64280180-C-A is Benign according to our data. Variant chr4-64280180-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3454624.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000511997.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECRL	NM_001010874.5	MANE Select	c.984G>T	p.Leu328Leu	synonymous	Exon 12 of 12	NP_001010874.2
	TECRL	NM_001363796.1		c.964+861G>T		intron	N/A	NP_001350725.1	E9PD39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECRL	ENST00000511997.1	TSL:1	c.83G>T	p.Ter28Leuext*?	stop_lost	Exon 2 of 2	ENSP00000423975.1	H0Y9F0
	TECRL	ENST00000381210.8	TSL:1 MANE Select	c.984G>T	p.Leu328Leu	synonymous	Exon 12 of 12	ENSP00000370607.3	Q5HYJ1
	TECRL	ENST00000941916.1		c.1209G>T	p.Leu403Leu	synonymous	Exon 13 of 13	ENSP00000611975.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151726 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000480 AC: 1 AN: 208146 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000676

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384838 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 686146

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30116

American (AMR) AF: 0.00 AC: 0 AN: 31710

Ashkenazi Jewish (ASJ) AF: 0.0000429 AC: 1 AN: 23310

East Asian (EAS) AF: 0.00 AC: 0 AN: 37754

South Asian (SAS) AF: 0.00 AC: 0 AN: 70930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077672

Other (OTH) AF: 0.0000176 AC: 1 AN: 56740

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0448430), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151844 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74202

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67872

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000291 AC: 1 AN: 3446

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	2.1
DANN	Benign	0.51
Eigen	Benign	0.025
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		1.3
GERP RS		2.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 19

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

Other links and lift over

dbSNP: rs563042010; hg19: chr4-65145898;