NM_015271.5:c.111T>A

Variant names:

• chr4-153270415-T-A
• NM_015271.5:c.111T>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S37N) has been classified 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
• Publications: 0 publications found

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]

TRIM2 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease type 2R

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000288637 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40135586).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015271.5. 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
	TRIM2	NM_015271.5	MANE Select	c.111T>A	p.Ser37Arg	missense	Exon 2 of 12	NP_056086.2	Q9C040-2
	TRIM2	NM_001375488.1		c.111T>A	p.Ser37Arg	missense	Exon 2 of 13	NP_001362417.1
	TRIM2	NM_001375489.1		c.108T>A	p.Ser36Arg	missense	Exon 2 of 13	NP_001362418.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRIM2	ENST00000338700.10	TSL:1 MANE Select	c.111T>A	p.Ser37Arg	missense	Exon 2 of 12	ENSP00000339659.5	Q9C040-2
	ENSG00000288637	ENST00000675838.1		c.30T>A	p.Ser10Arg	missense	Exon 2 of 18	ENSP00000501593.1	A0A6Q8PF18
	TRIM2	ENST00000437508.7	TSL:1	c.30T>A	p.Ser10Arg	missense	Exon 2 of 12	ENSP00000415812.2	Q9C040-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease type 2R (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.73
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.75
MutPred		0.39		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
Mutation Taster		=37/63	disease causing

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

hg19: chr4-154191567;