4-153270414-G-A

Variant names:

• chr4-153270414-G-A
• rs1311672657
• NM_015271.5:c.110G>A

Variant summary

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

The NM_015271.5(TRIM2):​c.110G>A​(p.Ser37Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. S37R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRIM2 NM_015271.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.88

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40131682).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM2	NM_015271.5	c.110G>A	p.Ser37Asn	missense_variant	Exon 2 of 12	ENST00000338700.10	NP_056086.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM2	ENST00000338700.10	c.110G>A	p.Ser37Asn	missense_variant	Exon 2 of 12	1	NM_015271.5	ENSP00000339659.5
ENSG00000288637	ENST00000675079.1	c.29G>A	p.Ser10Asn	missense_variant	Exon 2 of 18			ENSP00000502677.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251276 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135806

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: 0.00000205 AC: 3 AN: 1461770 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 10 of the TRIM2 protein (p.Ser10Asn). This variant is present in population databases (no rsID available, gnomAD 0.006%). 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	0.63
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;T;.;.;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;D;D;D;.;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.034	T
MutationAssessor	Benign	1.5	.;L;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.6	N;N;.;N;.;.;.
REVEL	Benign	0.24
Sift	Benign	0.054	T;D;.;D;.;.;.
Sift4G	Uncertain	0.023	D;D;D;D;D;T;D
Polyphen		0.98	D;D;.;.;.;.;.
Vest4		0.67, 0.63, 0.64, 0.61, 0.58
MutPred		0.36		Loss of catalytic residue at S10 (P = 0.0416);Loss of catalytic residue at S10 (P = 0.0416);Loss of catalytic residue at S10 (P = 0.0416);.;Loss of catalytic residue at S10 (P = 0.0416);Loss of catalytic residue at S10 (P = 0.0416);Loss of catalytic residue at S10 (P = 0.0416);
MVP		0.44
MPC		1.7
ClinPred		0.78	D
GERP RS		5.7
Varity_R		0.35
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1311672657; hg19: chr4-154191566;