1-26053931-T-G

Variant names:

• chr1-26053931-T-G
• rs1471997851
• NM_032588.4:c.1013A>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032588.4(TRIM63):​c.1013A>C​(p.Asp338Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,441,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: TRIM63 NM_032588.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.283
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048555315).

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.1013A>C	p.Asp338Ala	missense	Exon 8 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.1013A>C	p.Asp338Ala	missense	Exon 8 of 9	ENSP00000363390.3	Q969Q1-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 231338 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 21 AN: 1441574 Hom.: 0 Cov.: 29 AF XY: 0.0000181 AC XY: 13 AN XY: 717680

African (AFR) AF: 0.00 AC: 0 AN: 31938

American (AMR) AF: 0.00 AC: 0 AN: 37164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25336

East Asian (EAS) AF: 0.00 AC: 0 AN: 39106

South Asian (SAS) AF: 0.00 AC: 0 AN: 83208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000190 AC: 21 AN: 1106440

Other (OTH) AF: 0.00 AC: 0 AN: 59498

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.52
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.28
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.036
Sift	Benign	0.74	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.20		Gain of helix (P = 0.027)
MVP		0.31
MPC		0.21
ClinPred		0.060	T
GERP RS		2.1
Varity_R		0.097
gMVP		0.12
Mutation Taster		=95/5	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: rs1471997851; hg19: chr1-26380422;