rs148395034

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PVS1BS2

The NM_032588.4(TRIM63):c.739C>T(p.Gln247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,614,210 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00050 ( 4 hom. )

Consequence

TRIM63
NM_032588.4 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:3B:1

Conservation

PhyloP100: 0.851

Publications

21 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BS2

High Homozygotes in GnomAdExome4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032588.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM63	NM_032588.4	MANE Select	c.739C>T	p.Gln247*	stop_gained	Exon 5 of 9	NP_115977.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM63	ENST00000374272.4	TSL:1 MANE Select	c.739C>T	p.Gln247*	stop_gained	Exon 5 of 9	ENSP00000363390.3

Frequencies

GnomAD3 genomes

AF:

0.000558

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000981

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000700

AC:

176

AN:

251478

AF XY:

0.000647

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000491

Gnomad ASJ exome

AF:

0.00794

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.000501

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000502

AC:

734

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000462

AC XY:

336

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000447

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00727

AC:

190

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000580

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000694

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000389

AC:

433

AN:

1112012

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

142

189

236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000551

AC:

AN:

152318

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41562

American (AMR)

AF:

0.000915

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00692

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000470

AC:

AN:

68038

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000730

Hom.:

Bravo

AF:

0.000510

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000486

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Pathogenic:3Uncertain:2

Zaffran Lab, Genetics of Cardiac Diseases Laboratory, Marseille Medical Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with hypertrophic cardiomyopathy (MONDO:0005045), TRIM63-related. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (810 heterozygotes, 4 homozygotes). (SP) 0708 - Other NMD-predicted variants comparable to the one identified in this case have conflicting previous evidence for pathogenicity. At least five other NMD-predicted variants have been reported, including in homozygous and compound heterozygous individuals with HCM, with VUS and pathogenic classifications (ClinVar, PMIDs: 38757491, 32451364). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in multiple homozygous and compound heterozygous individuals with hypertrophic cardiomyopathy; heterozygous family members were unaffected (PMIDs: 30372688, 25801283, 32451364, 35273634, 37431535, 32659924). It has also been classified as likely benign, VUS and likely pathogenic/pathogenic by clinical laboratories in ClinVar. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has shown to segregate in homozygous and compound heterozygous families with HCM (PMIDs: 32451364, 25801283, 32659924). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Jul 07, 2021

Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 21, 2024

Genomics, Clalit Research Institute, Clalit Health Care

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frequency: The variant is rare, observed in 192 alleles out of 282,876 (0.067874%) in the gnomAD2 reference population dataset (PM2_support). Frequency among cases: This variant has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (PMID:24436435 , 32451364) (PS4). Variant type: Null variant in a gene where loss of function is probably mechanism of disease (PVS1). Clinical evidence: This variant has previously been described in ClinVar (VCV222849) with the following classifications: LB (1) / VUS (2) / P (1) / LP (1). Gene coverage: 100% of TRIM63 is covered with at least 10x.

Institute of Human Genetics, University of Wuerzburg

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

Primary familial hypertrophic cardiomyopathy

Pathogenic:2Uncertain:1

Aug 20, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TRIM63 c.739C>T (p.Gln247X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0007 in 251478 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TRIM63 causing Hypertrophic Cardiomyopathy (0.0007 vs 0.005), allowing no conclusion about variant significance. c.739C>T has been reported in the literature in individuals affected with Hypertrophic Cardiomyopathy (e.g. Chen_2013, Olive_2015, Jokela_2019, Salazar-Mendiguchia_2020, Andreeva_2022), primarily affecting homozygous and compound heterozygous individuals. Confirmed heterozygous carriers were unaffected (e.g. Ploski_2014, Olive_2015, Salazar-Mendiguchia_2020, Andreeva_2022). In vitro analysis of the variant in HeLa cells showed the variant completely abolished normal ubiquitination activity, which resulted in elevated levels of MYH6 and MYBPC3 levels (Chen_2013). In mice, transgenic 247* animals all showed evidence of ventricular wall thickening, which was reversed when the transgene was turned off (Chen_2013). The following publications have been ascertained in the context of this evaluation (PMID: 24436435, 32451364, 35273634, 22821932, 30372688, 25801283). ClinVar contains an entry for this variant (Variation ID: 222849). Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 20, 2015

Blueprint Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Institute of Human Genetics, Medical University Innsbruck

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Pathogenic:1Benign:1

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 11, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP4, PS3_supporting, PS4, PVS1

Inborn genetic diseases

Pathogenic:1

Mar 14, 2024

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.739C>T (p.Q247*) alteration, located in coding exon 5 of the TRIM63 gene, consists of a C to T substitution at nucleotide position 739. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 247. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.068% (192/282876) total alleles studied. The highest observed frequency was 0.81% (84/10370) of Ashkenazi Jewish alleles. This variant has been identified in the homozygous state and compound heterozygous with another TRIM63 variant in multiple individuals with features consistent with TRIM63-related hypertrophic cardiomyopathy (Olivé, 2015; Jokela, 2019; Salazar-Mendiguchía, 2020; Andreeva, 2022). Induced expression of the TRIM63 p.Q247* alteration in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of hypertrophic markers, which were normalized on turning off expression of the mutant protein (Chen, 2012). Functional analysis of the variant in HeLa cells and cardiac myocytes indicated a defect in E3 ligase activity as revealed by impaired auto-ubiquitination as well as ubiquitination and subsequent degradation of TRIM63 substrates, MYH6 and MYBPC3 (Chen, 2012). However it is important to note that these expression studies were performed using a cDNA construct which likely has different physiological effects than the genomic fragment (dominant negative vs. loss of function). Based on the available evidence, this alteration is classified as pathogenic.

CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 31

Pathogenic:1

Sep 14, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Cardiovascular phenotype

Pathogenic:1

Sep 11, 2023

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.68

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Benign

0.67

PhyloP100

0.85

Vest4

0.92

GERP RS

5.5

Mutation Taster

=15/185

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over