11-6456410-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_033278.4(TRIM3):c.1316G>C(p.Gly439Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 1,531,032 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: TRIM3 NM_033278.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.56

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 Benign. Variant got -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIM3
• BP4: Computational evidence support a benign effect (MetaRNN=0.026162267).
• BP6: Variant 11-6456410-C-G is Benign according to our data. Variant chr11-6456410-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2357516.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM3	NM_033278.4	c.1316G>C	p.Gly439Ala	missense_variant	6/12	ENST00000345851.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM3	ENST00000345851.8	c.1316G>C	p.Gly439Ala	missense_variant	6/12	1	NM_033278.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000954 AC: 18 AN: 188750 Hom.: 0 AF XY: 0.0000900 AC XY: 9 AN XY: 100002

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000228

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.0000674 AC: 93 AN: 1378906 Hom.: 0 Cov.: 34 AF XY: 0.0000547 AC XY: 37 AN XY: 675808

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000295

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000842

Gnomad4 OTH exome AF: 0.000353

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000743 Hom.: 0

Bravo AF: 0.000110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000750 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.1316G>C (p.G439A) alteration is located in exon 7 (coding exon 5) of the TRIM3 gene. This alteration results from a G to C substitution at nucleotide position 1316, causing the glycine (G) at amino acid position 439 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

TRIM3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.022	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.13	T;T;.;T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.060
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.026	T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N;N;.;N;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.35	N;N;N;N;.
REVEL	Benign	0.21
Sift	Benign	0.14	T;T;T;T;.
Sift4G	Benign	0.63	T;T;T;T;.
Polyphen		0.070	B;B;.;B;.
Vest4		0.29
MVP		0.44
MPC		1.2
ClinPred		0.089	T
GERP RS		5.1
Varity_R		0.15
gMVP		0.53

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

Other links and lift over

dbSNP: rs368164162; hg19: chr11-6477640;