3-160438201-T-C

Position:

• chr3-160438201-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173084.3(TRIM59):​c.983A>G​(p.Lys328Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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)
• Consequence: TRIM59 NM_173084.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

Genes affected

TRIM59 (HGNC:30834): (tripartite motif containing 59) Predicted to enable ubiquitin protein ligase activity. Acts upstream of or within negative regulation of I-kappaB kinase/NF-kappaB signaling. Predicted to be located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000248710 (HGNC:56756): (TRIM59-IFT80 readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring TRIM59 (tripartite motif containing 59) and IFT80 (intraflagellar transport 80) genes on chromosome 3. The readthrough transcript is unlikely to produce a protein product. [provided by RefSeq, Jun 2017]

ACMG classification

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=0.16009903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRIM59	NM_173084.3	c.983A>G	p.Lys328Arg	missense_variant	3/3	ENST00000309784.9	NP_775107.1
TRIM59-IFT80	NR_148401.1	n.1147+31A>G		intron_variant
TRIM59-IFT80	NR_148402.1	n.1077+31A>G		intron_variant
TRIM59-IFT80	NR_148403.1	n.1344+31A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRIM59	ENST00000309784.9	c.983A>G	p.Lys328Arg	missense_variant	3/3	1	NM_173084.3	ENSP00000311219.4
ENSG00000248710	ENST00000483754.1	n.952+31A>G		intron_variant		2		ENSP00000456272.1
TRIM59	ENST00000543469.1	c.952+31A>G		intron_variant		5		ENSP00000444313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Mar 14, 2023

The c.983A>G (p.K328R) alteration is located in exon 3 (coding exon 1) of the TRIM59 gene. This alteration results from a A to G substitution at nucleotide position 983, causing the lysine (K) at amino acid position 328 to be replaced by an arginine (R). 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	0.080
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.018	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.059
Sift	Benign	0.16	T
Sift4G	Benign	0.51	T
Polyphen		0.78	P
Vest4		0.14
MutPred		0.37		Loss of methylation at K328 (P = 0.0068);
MVP		0.38
MPC		0.062
ClinPred		0.29	T
GERP RS		5.8
Varity_R		0.035
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs978390841; hg19: chr3-160155989;