chr4-153270415-T-A

Position:

• chr4-153270415-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015271.5(TRIM2):​c.111T>A​(p.Ser37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.729

Genes affected

TRIM2 (HGNC:15974): (tripartite motif containing 2) The protein encoded by this gene is a member of the tripartite motif (TRIM) family. The TRIM motif includes three zinc-binding domains, a RING, a B-box type 1 and a B-box type 2, and a coiled-coil region. The protein localizes to cytoplasmic filaments. It plays a neuroprotective role and functions as an E3-ubiquitin ligase in proteasome-mediated degradation of target proteins. Mutations in this gene can cause early-onset axonal neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRIM2. . Gene score misZ 3.5715 (greater than the threshold 3.09). Trascript score misZ 3.9409 (greater than threshold 3.09). GenCC has associacion of gene with Charcot-Marie-Tooth disease type 2R.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40135586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM2	NM_015271.5	c.111T>A	p.Ser37Arg	missense_variant	2/12	ENST00000338700.10	NP_056086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM2	ENST00000338700.10	c.111T>A	p.Ser37Arg	missense_variant	2/12	1	NM_015271.5	ENSP00000339659

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 2R Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 17, 2024

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 10 of the TRIM2 protein (p.Ser10Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TRIM2-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;T;T;.;.;T;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;D;D;.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.8	.;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D;N;.;N;.;.;.
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D;D;.;D;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;.;.;.
Vest4		0.75, 0.68, 0.73, 0.78, 0.63
MutPred		0.39		Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);.;Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);Gain of solvent accessibility (P = 0.0766);
MVP		0.43
MPC		2.0
ClinPred		0.98	D
GERP RS		0.41
Varity_R		0.42
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-154191567;