Genetic Variant TRIM33:p.Ala761Thr (chr1-114407078-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_015906.4(TRIM33):c.2281G>A(p.Ala761Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRIM33
NM_015906.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Variant links:

Genes affected

TRIM33 (HGNC:16290): (tripartite motif containing 33) The protein encoded by this gene is thought to be a transcriptional corepressor. However, molecules that interact with this protein have not yet been identified. The protein is a member of the tripartite motif family. This motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. Three alternatively spliced transcript variants for this gene have been described, however, the full-length nature of one variant has not been determined. [provided by RefSeq, Jul 2008]

TRIM33 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054066777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM33	NM_015906.4 link	c.2281G>A	p.Ala761Thr	missense_variant	Exon 14 of 20	ENST00000358465.7	NP_056990.3	Q9UPN9-1B3KN30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIM33	ENST00000358465.7 link	c.2281G>A	p.Ala761Thr	missense_variant	Exon 14 of 20	1	NM_015906.4	ENSP00000351250.2	Q9UPN9-1
TRIM33	ENST00000369543.6 link	c.2281G>A	p.Ala761Thr	missense_variant	Exon 14 of 19	1		ENSP00000358556.2	Q9UPN9-2
TRIM33	ENST00000448034.5 link	c.1561G>A	p.Ala521Thr	missense_variant	Exon 12 of 18	5		ENSP00000402333.1	H0Y612
TRIM33	ENST00000476908.1 link	n.-111G>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250818

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135580

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS 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:

0.00000137

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726922

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2281G>A (p.A761T) alteration is located in exon 14 (coding exon 14) of the TRIM33 gene. This alteration results from a G to A substitution at nucleotide position 2281, causing the alanine (A) at amino acid position 761 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.084

T;.

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.95

L;L

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.20

N;N

REVEL

Benign

0.11

Sift

Benign

0.16

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.0

B;B

Vest4

0.042

MutPred

0.18

Gain of phosphorylation at A761 (P = 0.0103);Gain of phosphorylation at A761 (P = 0.0103);

MVP

0.23

MPC

0.53

ClinPred

0.21

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.024

gMVP

0.21

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