NM_173084.3:c.1189G>T

Variant names:

• chr3-160437995-C-A
• rs895274943
• NM_173084.3:c.1189G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_173084.3(TRIM59):​c.1189G>T​(p.Val397Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,552,130 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TRIM59 NM_173084.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.335
• Publications: 1 publications found

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-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]

ACMG classification

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=0.019620568).

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

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

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1399982 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 691944

African (AFR) AF: 0.00 AC: 0 AN: 30798

American (AMR) AF: 0.00 AC: 0 AN: 31496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22376

East Asian (EAS) AF: 0.00 AC: 0 AN: 39116

South Asian (SAS) AF: 0.00 AC: 0 AN: 75036

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5472

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086860

Other (OTH) AF: 0.0000173 AC: 1 AN: 57654

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0080
DANN	Benign	0.44
DEOGEN2	Benign	0.0046	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.020	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-0.34
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0090
Sift	Benign	1.0	T
Sift4G	Benign	0.84	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.21		Gain of ubiquitination at K399 (P = 0.1162)
MVP		0.081
MPC		0.059
ClinPred		0.036	T
GERP RS		-3.2
Varity_R		0.027
gMVP		0.065
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs895274943; hg19: chr3-160155783;