1-114424726-C-A

Variant names:

• chr1-114424726-C-A
• rs771084521
• NM_015906.4:c.1725G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015906.4(TRIM33):​c.1725G>T​(p.Met575Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,240 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 6.9e-7 (0 hom.)
• Consequence: TRIM33 NM_015906.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15406778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM33	NM_015906.4	c.1725G>T	p.Met575Ile	missense_variant	Exon 10 of 20	ENST00000358465.7	NP_056990.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM33	ENST00000358465.7	c.1725G>T	p.Met575Ile	missense_variant	Exon 10 of 20	1	NM_015906.4	ENSP00000351250.2
TRIM33	ENST00000369543.6	c.1725G>T	p.Met575Ile	missense_variant	Exon 10 of 19	1		ENSP00000358556.2
TRIM33	ENST00000448034.5	c.933G>T	p.Met311Ile	missense_variant	Exon 7 of 18	5		ENSP00000402333.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452240 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722366

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1725G>T (p.M575I) alteration is located in exon 10 (coding exon 10) of the TRIM33 gene. This alteration results from a G to T substitution at nucleotide position 1725, causing the methionine (M) at amino acid position 575 to be replaced by an isoleucine (I). 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	Uncertain	0.38
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.84	N;N
REVEL	Benign	0.16
Sift	Benign	0.35	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.14	B;B
Vest4		0.27
MutPred		0.35		Loss of MoRF binding (P = 0.0921);Loss of MoRF binding (P = 0.0921);
MVP		0.46
MPC		0.58
ClinPred		0.45	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.066

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: rs771084521; hg19: chr1-114967348;