1-155177241-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_025058.5(TRIM46):c.860C>T(p.Thr287Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000867 in 1,614,058 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T287K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: TRIM46 NM_025058.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRIM46
• BP4: Computational evidence support a benign effect (MetaRNN=0.06459999).
• BS2: High AC in GnomAd at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRIM46	NM_025058.5	c.860C>T	p.Thr287Met	missense_variant	5/10	ENST00000334634.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRIM46	ENST00000334634.9	c.860C>T	p.Thr287Met	missense_variant	5/10	1	NM_025058.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000795 AC: 20 AN: 251432 Hom.: 0 AF XY: 0.0000957 AC XY: 13 AN XY: 135882

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: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000908 AC XY: 66 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152176 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74344

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000433 Hom.: 0

Bravo AF: 0.0000680

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Oct 03, 2022

The c.860C>T (p.T287M) alteration is located in exon 5 (coding exon 5) of the TRIM46 gene. This alteration results from a C to T substitution at nucleotide position 860, causing the threonine (T) at amino acid position 287 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	0.064
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.;.;.;T;.;T;T
Eigen	Benign	-0.070
Eigen_PC	Benign	0.063
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.065	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.82	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.96	N;.;N;.;N;N;N;.
REVEL	Benign	0.077
Sift	Benign	0.099	T;.;T;.;T;T;T;.
Sift4G	Benign	0.066	T;T;T;T;T;T;T;T
Polyphen		0.89, 0.66, 0.51	.;.;P;.;P;.;P;.
Vest4		0.13
MVP		0.28
MPC		1.1
ClinPred		0.066	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.43

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: rs376400786; hg19: chr1-155149717;