Genetic Variant TRIM46:p.Ala132Gly (chr1-155175957-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_025058.5(TRIM46):c.395C>G(p.Ala132Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,456,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 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: 0.0000034 ( 0 hom. )

Consequence

TRIM46
NM_025058.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.783

Variant links:

Genes affected

TRIM46 (HGNC:19019): (tripartite motif containing 46) This gene encodes a protein of the tripartite motif (TRIM) family. The TRIM motif includes zinc-binding domains, a RING finger region, a B-box motif and a coiled-coil domain. TRIM46 is reported to be involved in the proliferation of multiple types of cancer cells including lung and breast cancer. It has also been shown to control neuronal polarity and axon specification by forming uniform microtubule bundles in the axon. [provided by RefSeq, May 2022]

TRIM46 links:

ENSG00000273088 (HGNC:):

ENSG00000273088 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM46	NM_025058.5 link	c.395C>G	p.Ala132Gly	missense_variant	Exon 3 of 10	ENST00000334634.9	NP_079334.3	Q7Z4K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRIM46	ENST00000334634.9 link	c.395C>G	p.Ala132Gly	missense_variant	Exon 3 of 10	1	NM_025058.5	ENSP00000334657.4		Q7Z4K8-1
ENSG00000273088	ENST00000473363.3 link	c.49-2483G>C		intron_variant	Intron 1 of 4	5		ENSP00000477381.3		V9GZ38

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1456940

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724052

show subpopulations

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:

0.00000361

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395C>G (p.A132G) alteration is located in exon 3 (coding exon 3) of the TRIM46 gene. This alteration results from a C to G substitution at nucleotide position 395, causing the alanine (A) at amino acid position 132 to be replaced by a glycine (G). 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

Benign

0.10

BayesDel_addAF

Benign

-0.071

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.0054

T;.;.;.;T;.;T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.79

T;T;T;T;T;T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.20

.;.;N;N;.;.;N;.

PrimateAI

Uncertain

0.57

PROVEAN

Benign

0.48

N;.;N;.;N;N;N;.

REVEL

Benign

0.086

Sift

Benign

1.0

T;.;T;.;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T

Polyphen

0.40, 0.0020, 0.0010

.;.;B;.;B;.;B;.

Vest4

0.18

MutPred

0.42

.;.;Gain of disorder (P = 0.1717);Gain of disorder (P = 0.1717);Gain of disorder (P = 0.1717);.;Gain of disorder (P = 0.1717);.;

MVP

0.59

MPC

0.77

ClinPred

0.19

GERP RS

5.4

Varity_R

0.12

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.32

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over