rs140523053

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

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:2B:5

Conservation

PhyloP100: 9.99

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

hypertrophic cardiomyopathy
Inheritance: AR, AD Classification: MODERATE, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

TRIM63 links:

ENSG00000309383 (HGNC:):

ENSG00000309383 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

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

BP6

Variant 1-26067352-G-A is Benign according to our data. Variant chr1-26067352-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180559.

BS2

High Homozygotes in GnomAdExome4 at 8 AR,AD 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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRIM63	ENST00000374272.4 link	c.143C>T	p.Ala48Val	missense_variant	Exon 1 of 9	1	NM_032588.4	ENSP00000363390.3
TRIM63	ENST00000483052.1 link	n.1085C>T		non_coding_transcript_exon_variant	Exon 1 of 3	2
ENSG00000309383	ENST00000840652.1 link	n.187+891G>A		intron_variant	Intron 1 of 1

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

GnomAD2 exomes

AF:

0.00138

AC:

345

AN:

250842

AF XY:

0.00157

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 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

African (AFR)

AF:

0.000448

AC:

AN:

33478

American (AMR)

AF:

0.00121

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000858

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.000871

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.00280

AC:

3113

AN:

1111990

Other (OTH)

AF:

0.00139

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

197

394

590

787

984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

248

372

496

620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00127

AC:

193

AN:

152284

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41560

American (AMR)

AF:

0.00157

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00104

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00215

AC:

146

AN:

68026

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00180

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:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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

- -

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TRIM63: BS2 -

Cardiovascular phenotype

Uncertain:1

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_mod, PP3, BS1, BP6 -

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

(source)

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

PhyloP100

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

PromoterAI

0.027

Neutral

(source)

Varity_R

0.86

gMVP

0.62

Mutation Taster

=36/64

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over