rs148395034

chr1-26058482-G-Achr1-26058482-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_032588.4(TRIM63):c.739C>T(p.Gln247Ter) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:2 B:1
• Conservation: PhyloP100: 0.851

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM4: Stoplost variant in NM_032588.4 Downstream stopcodon found after 8 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM63	NM_032588.4	c.739C>T	p.Gln247Ter	stop_gained	5/9	ENST00000374272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM63	ENST00000374272.4	c.739C>T	p.Gln247Ter	stop_gained	5/9	1	NM_032588.4	P1

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152200 Hom.: 0 Cov.: 32

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

GnomAD3 exomes AF: 0.000700 AC: 176 AN: 251478 Hom.: 0 AF XY: 0.000647 AC XY: 88 AN XY: 135918

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 SAS exome AF: 0.0000327

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.: 4 Cov.: 31 AF XY: 0.000462 AC XY: 336 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00727

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000844

GnomAD4 genome AF: 0.000551 AC: 84 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00692

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00104

Gnomad4 NFE AF: 0.000470

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000765 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000654

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypertrophic cardiomyopathy Pathogenic:2 Uncertain:1

Likely pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, University of Wuerzburg	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomics, Clalit Research Institute, Clalit Health Care	Mar 21, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Jul 07, 2021	- -

Primary familial hypertrophic cardiomyopathy Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Medical University Innsbruck	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	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. 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, assuming autosomal recessive inheritance), 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). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as pathogenic, two as uncertain significance, and one as likely benign. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2024

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	43
Dann	Uncertain	1.0
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Benign	0.67	D
MutationTaster	Benign	1.0	A
Vest4		0.92
GERP RS		5.5

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

Other links and lift over

dbSNP: rs148395034; hg19: chr1-26384973;