1-26058416-C-T

Position:

chr1-26058416-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_032588.4(TRIM63):c.805G>A(p.Glu269Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00408 in 1,614,160 control chromosomes in the GnomAD database, including 27 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 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 26 hom. )

Consequence

TRIM63
NM_032588.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.03

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03695962).

BP6

Variant 1-26058416-C-T is Benign according to our data. Variant chr1-26058416-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 806097.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr1-26058416-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 26 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM63	NM_032588.4 linkuse as main transcript	c.805G>A	p.Glu269Lys	missense_variant	5/9	ENST00000374272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM63	ENST00000374272.4 linkuse as main transcript	c.805G>A	p.Glu269Lys	missense_variant	5/9	1	NM_032588.4	P1	Q969Q1-1

Frequencies

GnomAD3 genomes

AF:

0.00301

AC:

458

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00547

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.00314

AC:

786

AN:

250692

Hom.:

AF XY:

0.00325

AC XY:

441

AN XY:

135582

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00384

Gnomad NFE exome

AF:

0.00589

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00419

AC:

6129

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00406

AC XY:

2956

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.000497

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00363

Gnomad4 NFE exome

AF:

0.00518

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00301

AC:

458

AN:

152286

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

225

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.000588

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00547

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.00418

Hom.:

Bravo

AF:

0.00264

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00337

AC:

409

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00436

EpiControl

AF:

0.00516

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TRIM63: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 25, 2023	- -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, no assertion criteria provided

research

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

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Mar 11, 2024

Variant summary: TRIM63 c.805G>A (p.Glu269Lys) results in a conservative amino acid change located in the COS domain (IPR017903) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 250692 control chromosomes, predominantly at a frequency of 0.0059 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately one-fold of the estimated maximal expected allele frequency for a pathogenic variant in TRIM63 causing Hypertrophic Cardiomyopathy phenotype (0.005), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.805G>A has been reported in the literature in unspecified individuals affected with Hypertrophic Cardiomyopathy as well as in the control cohort, without strong evidence for causality (Chen_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hypertrophic Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 22821932). ClinVar contains an entry for this variant (Variation ID: 806097). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0080

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.15

Sift

Benign

0.036

Sift4G

Uncertain

0.044

Polyphen

0.99

Vest4

0.84

MVP

0.69

MPC

0.20

ClinPred

0.043

GERP RS

5.5

Varity_R

0.51

gMVP

0.71

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