Genetic Variant TRIM35:p.Ala455Thr (chr8-27287669-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_171982.5(TRIM35):c.1363G>A(p.Ala455Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,457,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 0.000010 ( 0 hom. )

Consequence

TRIM35
NM_171982.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23

Variant links:

Genes affected

TRIM35 (HGNC:16285): (tripartite motif containing 35) 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 function of this protein has not been identified. [provided by RefSeq, Jul 2008]

TRIM35 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22621033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRIM35	NM_171982.5 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 6 of 6	ENST00000305364.9	NP_741983.2	Q9UPQ4-1
TRIM35	XM_047421602.1 link	c.913G>A	p.Ala305Thr	missense_variant	Exon 6 of 6		XP_047277558.1
TRIM35	NM_001362813.2 link	c.*443G>A		3_prime_UTR_variant	Exon 5 of 5		NP_001349742.1
TRIM35	NM_001304495.2 link	c.*443G>A		3_prime_UTR_variant	Exon 4 of 4		NP_001291424.1	E5RGB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TRIM35	ENST00000305364.9 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 6 of 6	1	NM_171982.5	ENSP00000301924.4	Q9UPQ4-1
TRIM35	ENST00000521283.1 link	c.288+367G>A		intron_variant	Intron 4 of 4	2		ENSP00000429356.1	H0YBF3
TRIM35	ENST00000521253.1 link	c.*443G>A		downstream_gene_variant		1		ENSP00000428770.1	E5RGB3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000416

AC:

AN:

240552

Hom.:

AF XY:

0.00

AC XY:

AN XY:

130110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000920

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1457770

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

724746

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1363G>A (p.A455T) alteration is located in exon 6 (coding exon 6) of the TRIM35 gene. This alteration results from a G to A substitution at nucleotide position 1363, causing the alanine (A) at amino acid position 455 to be replaced by a threonine (T). 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

0.11

BayesDel_addAF

Benign

-0.086

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.014

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.83

M_CAP

Benign

0.059

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.6

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.75

REVEL

Benign

0.13

Sift

Benign

0.35

Sift4G

Benign

1.0

Polyphen

0.57

Vest4

0.24

MutPred

0.65

Gain of sheet (P = 0.0827);

MVP

0.77

MPC

0.89

ClinPred

0.59

GERP RS

4.3

Varity_R

0.039

gMVP

0.32

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over