chr6-30170602-T-C

Position:

• chr6-30170602-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033229.3(TRIM15):​c.833T>C​(p.Met278Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000021 (0 hom.)
• Consequence: TRIM15 NM_033229.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.93

Genes affected

TRIM15 (HGNC:16284): (tripartite motif containing 15) 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 protein localizes to the cytoplasm. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

TRIM15 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2966439).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM15	NM_033229.3	c.833T>C	p.Met278Thr	missense_variant	5/7	ENST00000376694.9	NP_150232.2
TRIM15	XM_011514987.2	c.518T>C	p.Met173Thr	missense_variant	6/8		XP_011513289.1
TRIM15	XM_011514988.3	c.212T>C	p.Met71Thr	missense_variant	3/5		XP_011513290.1
TRIM15	XM_047419503.1	c.*96T>C		downstream_gene_variant			XP_047275459.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM15	ENST00000376694.9	c.833T>C	p.Met278Thr	missense_variant	5/7	1	NM_033229.3	ENSP00000365884.4
TRIM15	ENST00000619857.4	c.626T>C	p.Met209Thr	missense_variant	6/8	5		ENSP00000484001.1
TRIM15	ENST00000433744.1	c.341T>C	p.Met114Thr	missense_variant	3/5	3		ENSP00000398285.1
TRIM15	ENST00000477944.1	n.290T>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461488 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727076

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Feb 15, 2023

The c.833T>C (p.M278T) alteration is located in exon 5 (coding exon 5) of the TRIM15 gene. This alteration results from a T to C substitution at nucleotide position 833, causing the methionine (M) at amino acid position 278 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	.;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	.;D
REVEL	Benign	0.088
Sift	Benign	0.075	.;T
Sift4G	Benign	0.085	T;T
Polyphen		0.012	.;B
Vest4		0.35
MutPred		0.69		.;Loss of stability (P = 0.0862);
MVP		0.49
MPC		0.46
ClinPred		0.81	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.30

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: rs1430117100; hg19: chr6-30138379;