rs61749355

Variant names:

• chr1-26058416-C-T
• rs61749355
• NM_032588.4:c.805G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-26058416-C-T
• chr1-26058416-C-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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). Synonymous variant affecting the same amino acid position (i.e. E269E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (26 hom.)
• Consequence: TRIM63 NM_032588.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.03
• Publications: 9 publications found

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: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 806097.
• BS2: High Homozygotes in GnomAdExome4 at 26 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM63	NM_032588.4	MANE Select	c.805G>A	p.Glu269Lys	missense	Exon 5 of 9	NP_115977.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM63	ENST00000374272.4	TSL:1 MANE Select	c.805G>A	p.Glu269Lys	missense	Exon 5 of 9	ENSP00000363390.3	Q969Q1-1

Frequencies

GnomAD3 genomes AF: 0.00301 AC: 458 AN: 152168 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00314 AC: 786 AN: 250692 AF XY: 0.00325

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 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.: 26 Cov.: 31 AF XY: 0.00406 AC XY: 2956 AN XY: 727238

African (AFR) AF: 0.000358 AC: 12 AN: 33478

American (AMR) AF: 0.000402 AC: 18 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000497 AC: 13 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00363 AC: 194 AN: 53420

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00518 AC: 5761 AN: 1112008

Other (OTH) AF: 0.00210 AC: 127 AN: 60394

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.00302 AC XY: 225 AN XY: 74466

African (AFR) AF: 0.000866 AC: 36 AN: 41574

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00367 AC: 39 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00547 AC: 372 AN: 68016

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.00420 Hom.: 7

Bravo AF: 0.00264

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00337 AC: 409

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00516

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	2	not specified (2)
-	1	-	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.15
Sift	Benign	0.036	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.84
MVP		0.69
MPC		0.20
ClinPred		0.043	T
GERP RS		5.5
Varity_R		0.51
gMVP		0.71
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs61749355; hg19: chr1-26384907; COSMIC: COSV65328122; COSMIC: COSV65328122;