11-6458234-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_033278.4(TRIM3):c.194C>T(p.Thr65Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRIM3 NM_033278.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59

Genes affected

TRIM3 (HGNC:10064): (tripartite motif containing 3) The protein encoded by this gene is a member of the tripartite motif (TRIM) family, also called the 'RING-B-box-coiled-coil' (RBCC) subgroup of RING finger proteins. 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. This protein localizes to cytoplasmic filaments. It is similar to a rat protein which is a specific partner for the tail domain of myosin V, a class of myosins which are involved in the targeted transport of organelles. The rat protein can also interact with alpha-actinin-4. Thus it is suggested that this human protein may play a role in myosin V-mediated cargo transport. Alternatively spliced transcript variants encoding the same isoform have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRIM3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM3	NM_033278.4	c.194C>T	p.Thr65Met	missense_variant	3/12	ENST00000345851.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM3	ENST00000345851.8	c.194C>T	p.Thr65Met	missense_variant	3/12	1	NM_033278.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The c.194C>T (p.T65M) alteration is located in exon 4 (coding exon 2) of the TRIM3 gene. This alteration results from a C to T substitution at nucleotide position 194, causing the threonine (T) at amino acid position 65 to be replaced by a methionine (M). 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	0.33
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;T;T;.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.9	L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N;N;N;.;D;D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0040	D;D;D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;.;.;.
Polyphen		1.0	D;D;D;.;.;.
Vest4		0.63
MutPred		0.67		Gain of disorder (P = 0.2528);Gain of disorder (P = 0.2528);Gain of disorder (P = 0.2528);.;Gain of disorder (P = 0.2528);Gain of disorder (P = 0.2528);
MVP		0.40
MPC		2.2
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.29
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6479464;