rs140523053

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_032588.4(TRIM63):c.143C>T(p.Ala48Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,614,000 control chromosomes in the GnomAD database, including 8 homozygotes. 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 0.0013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0023 ( 8 hom. )

Consequence

TRIM63
NM_032588.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 9.99

Variant links:

Genes affected

TRIM63 (HGNC:16007): (tripartite motif containing 63) This gene encodes a member of the RING zinc finger protein family found in striated muscle and iris. The product of this gene is an E3 ubiquitin ligase that localizes to the Z-line and M-line lattices of myofibrils. This protein plays an important role in the atrophy of skeletal and cardiac muscle and is required for the degradation of myosin heavy chain proteins, myosin light chain, myosin binding protein, and for muscle-type creatine kinase. [provided by RefSeq, Feb 2012]

TRIM63 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29423878).

BS2

High Homozygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM63	NM_032588.4 link	c.143C>T	p.Ala48Val	missense_variant	Exon 1 of 9	ENST00000374272.4	NP_115977.2	Q969Q1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM63	ENST00000374272.4 link	c.143C>T	p.Ala48Val	missense_variant	Exon 1 of 9	1	NM_032588.4	ENSP00000363390.3		Q969Q1-1
TRIM63	ENST00000483052.1 link	n.1085C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00127

AC:

193

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00138

AC:

345

AN:

250842

Hom.:

AF XY:

0.00157

AC XY:

213

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00227

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00230

AC:

3355

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

1693

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00121

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000858

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00280

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152284

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00215

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00187

Hom.:

Bravo

AF:

0.00142

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00125

AC:

152

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Jul 18, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ala48Val variant in the TRIM63 gene has been previously reported in two unrelated individuals with hypertrophic cardiomyopathy (Chen et al., 2012). This variant has been identified in 282/128,712 European non-Finnish chromosomes (372/282,236 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is higher than expected for a pathogenic variant. This variant is present in ClinVar (Variation ID: 180559). The alanine at position 48 is strongly evolutionarily conserved. Computational tools predict that the p.Ala48Val variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ala48Val variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BS1_Supporting; PP3. Has been recently associated with autosomal recessive hypertrophic cardiomyopathy, but this is not listed in databases. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRIM63: BS2 -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Primary familial hypertrophic cardiomyopathy

Benign:1

Jul 21, 2014

Blueprint Genetics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

TRIM63-related disorder

Benign:1

Mar 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

Eigen

Uncertain

0.65

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.020

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.17

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.92

MVP

0.75

MPC

0.69

ClinPred

0.071

GERP RS

5.7

Varity_R

0.86

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over