rs587777063

Positions:

• chr4-153294460-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_015271.5(TRIM2):​c.761A>T​(p.Glu254Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

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]

ENSG00000288637 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 4-153294460-A-T is Pathogenic according to our data. Variant chr4-153294460-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 83303.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM2	NM_015271.5	c.761A>T	p.Glu254Val	missense_variant	5/12	ENST00000338700.10	NP_056086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM2	ENST00000338700.10	c.761A>T	p.Glu254Val	missense_variant	5/12	1	NM_015271.5	ENSP00000339659.5
ENSG00000288637	ENST00000675079.1	c.680A>T	p.Glu227Val	missense_variant	5/18			ENSP00000502677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.084	D
MutationAssessor	Uncertain	2.4	M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.7	D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.50		Loss of helix (P = 0.079);Loss of helix (P = 0.079);.;
MVP		0.73
MPC		1.8
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.62
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587777063; hg19: chr4-154215612;