Genetic Variant TRIM59:p.Val397Leu (chr3-160437995-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_173084.3(TRIM59):c.1189G>C(p.Val397Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,399,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V397M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TRIM59
NM_173084.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.335

Publications

1 publications found

Variant links:

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]

TRIM59 links:

TRIM59-IFT80 (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]

TRIM59-IFT80 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.019610435).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173084.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRIM59	NM_173084.3	MANE Select	c.1189G>C	p.Val397Leu	missense	Exon 3 of 3	NP_775107.1	Q8IWR1-1
TRIM59-IFT80	NR_148401.1		n.1147+237G>C		intron	N/A
TRIM59-IFT80	NR_148402.1		n.1077+237G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRIM59	ENST00000309784.9	TSL:1 MANE Select	c.1189G>C	p.Val397Leu	missense	Exon 3 of 3	ENSP00000311219.4	Q8IWR1-1
TRIM59-IFT80	ENST00000483754.1	TSL:2	n.952+237G>C		intron	N/A	ENSP00000456272.1	H3BRJ5
TRIM59	ENST00000870881.1		c.1189G>C	p.Val397Leu	missense	Exon 4 of 4	ENSP00000540940.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1399984

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30798

American (AMR)

AF:

0.00

AC:

AN:

31496

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22376

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39116

South Asian (SAS)

AF:

0.00

AC:

AN:

75036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5472

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086862

Other (OTH)

AF:

0.00

AC:

AN:

57654

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0080

(source)

DANN

Benign

0.53

DEOGEN2

Benign

0.0046

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.34

M_CAP

Benign

0.0037

MetaRNN

Benign

0.020

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

PhyloP100

-0.34

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.16

REVEL

Benign

0.011

Sift

Benign

1.0

Sift4G

Benign

0.84

Polyphen

0.0

Vest4

0.042

MutPred

0.21

Gain of ubiquitination at K399 (P = 0.1162)

MVP

0.081

MPC

0.059

ClinPred

0.047

GERP RS

-3.2

Varity_R

0.027

gMVP

0.065

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over