4-64280154-GC-G

Variant names:

• chr4-64280154-GC-G
• rs1461307621
• NM_001010874.5:c.1009delG

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Moderate PP5

The NM_001010874.5(TECRL):​c.1009delG​(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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.15
• Publications: 1 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.

• 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 1 pathogenic variants in the truncated region.
• 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 VariationId is 1794643.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010874.5. 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.1009delG	p.Ala337HisfsTer9	frameshift	Exon 12 of 12	NP_001010874.2
	TECRL	NM_001363796.1		c.964+886delG		intron	N/A	NP_001350725.1	E9PD39

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TECRL	ENST00000381210.8	TSL:1 MANE Select	c.1009delG	p.Ala337HisfsTer9	frameshift	Exon 12 of 12	ENSP00000370607.3	Q5HYJ1
	TECRL	ENST00000511997.1	TSL:1	c.*24delG		3_prime_UTR	Exon 2 of 2	ENSP00000423975.1	H0Y9F0
	TECRL	ENST00000941916.1		c.1234delG	p.Ala412HisfsTer9	frameshift	Exon 13 of 13	ENSP00000611975.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151614 Hom.: 0 Cov.: 32

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

African (AFR) AF: 0.00 AC: 0 AN: 32758

American (AMR) AF: 0.00 AC: 0 AN: 42976

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25754

East Asian (EAS) AF: 0.00 AC: 0 AN: 38978

South Asian (SAS) AF: 0.00 AC: 0 AN: 83114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52902

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.0000687 AC: 76 AN: 1105472

Other (OTH) AF: 0.0000167 AC: 1 AN: 59714

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151614 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73998

African (AFR) AF: 0.00 AC: 0 AN: 41280

American (AMR) AF: 0.0000658 AC: 1 AN: 15196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10482

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67884

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Cardiovascular phenotype (1)
1	-	-	Catecholaminergic polymorphic ventricular tachycardia 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.1
Mutation Taster		=58/142	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1461307621; hg19: chr4-65145872;